Heterocyclyl compounds as MEK inhibitors

ABSTRACT

The present disclosure is related to heteroaryl compounds as MEK inhibitors. These compounds include heteroaryl compounds of formula I, their pharmaceutically acceptable salts, combinations with suitable medicament and pharmaceutical compositions thereof. The present disclosure also includes processes of preparation of the compounds and their use in methods of treatment. The compounds as disclosed herein are of Formula (I) below:

CROSS-REFERENCE TO A RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.15/218,980, filed on Jul. 25, 2016, which is a Continuation of U.S.patent application Ser. No. 14/385,092, filed on Dec. 11, 2014, now U.S.Pat. No. 9,428,499, which is the U.S. National Stage filing ofPCT/IB2013/051908 filed on Mar. 11, 2013, which claims the benefit ofIndian Provisional Patent Application No. 0288/KOL/2012 filed Mar. 14,2012, the disclosures of each of which are herein incorporated byreference in their entirety.

FIELD OF THE INVENTION

The present invention relates to anticancer compounds, theirpharmaceutically acceptable salts, combinations with suitable medicamentand pharmaceutical compositions thereof containing one or more suchcompounds, and methods of treating various cancers.

BACKGROUND OF THE INVENTION

Cancer cells possess certain characteristics that allow them a growthadvantage. These include six main alterations in cell physiology such asself-sufficiency in growth signals, insensitivity to growth-inhibitorysignals, evasion of apoptosis, indefinite proliferative potential,sustained angiogenesis, tissue invasion and metastasis (Hanahan andWeinberg, Cell, 2000, Vol. 100, 57-70). These changes are triggered bygenomic instability and inflammation which generates a microenvironmentconducive for tumor growth. In addition to the above mentioned traits,reprogramming of cellular energy metabolism and evasion of immunedestruction has also been observed in a majority of cancers.

The enhanced survival in cancer cells is further potentiated by thepresence of aberrantly activated signalling pathways. A large majorityof cancers are known to have mutations in growth factor signallingcascades that lead to constitutive activation of these pathways. Suchconstitutive activations has been observed in growth factor receptorswhich include but are not limited to epidermal growth factorreceptor—EGFR, fibroblast growth factor receptor—FGFR, Hepatocyte growthfactor receptor—HGFR, etc. Furthermore, activating mutations have beenreported in certain receptor as well as non receptor tyrosine kinaseswhich include but are not limited to MET receptor tyrosine kinase,EGFR-tyrosine kinase, Bcr-Abl tyrosine kinase, Src tyrosine kinase etc.Activation of Ser-Thr kinases such as Ras and lipid kinases such asPI3-kinases also leads to oncogenesis. Chronic activation of the growthfactor/cytokine/hormone-associated signalling leads to activation ofimmediate downstream components such as Src, Ras, PI3-kinase, etc. Thesekinases further activate effectors such as MEK, ERK, AKT, eventuallyleading to activation of transcription factors that endow the cells witha high proliferative potential, improved survival, subversion ofmetabolic pathways and inhibition of apoptosis. (Hanahan and Weinberg,Cell, 2000, Vol. 100, 57-70; Hanahan and Weinberg Cell 2011, Vol. 144,646-674).

MEK kinase (Mitogen Activated Protein Kinase Kinase (MAPKK)) is animportant component of the Ras-RAF-MEK-ERK cell survival pathway. TheRas pathway is activated by binding of growth factors, cytokines, andhormones to their cognate receptors. In cancer cells, this pathway is,however, constitutively activated and leads to increased cancer cellsurvival, cell proliferation, angiogenesis and metastasis. The tumorsthat show constitutive activation of the Ras or the MEK kinase includebut are not limited to those of the colon, pancreas, breast, brain,ovary, lungs and skin (Sebolt-Leopold and Herrera, Nat. Rev. Cancer2004, 4 937-947; Fukazawa et al., Mol. Cancer Ther. 2002, Vol. 1,303-309). Activation of Ras (due to upstream signalling or as a resultof activating point mutations in the Ras oncogene) lead to thephosphorylation and activation of Raf kinase that in turn phosphorylateand activate MEK kinase. MEK1/2 kinase phosphorylates and activates theERK1/2 kinase (also referred to as MAP Kinase) that furtherphosphorylates and regulates the function of proteins such as Mcl-1, Bimand Bad that are involved in cell survival and apoptosis. Thus,activation of this phosphorylation mediated cascade leads to enhancedcell proliferation, cell survival, decreased cell death that arenecessary for initiation and maintenance of the tumorigenic phenotype(Curr. Opin. Invest. Drugs, 2008, 9, 614).

The Ras-Raf-MEK-ERK cascade plays a pivotal role in survival andproliferation of cancer cells. As such, inhibition of this pathway atany of these levels would lead to the inhibition of cancer cell growth,proliferation and survival. Indeed, it has already been reported thatinhibition of Ras or Raf leads to inhibition of tumor growth in animalmodels as well as in cancer patients. However, the success with theseinhibitors has been limited to only certain types of cancers (e.g.Sorafenib which inhibits Raf kinase has been approved for renal cellcarcinoma). Hence, inhibiting MEK is a novel approach towardscontrolling this pathway in cancer cells. Moreover, the possibility ofdesigning allosteric inhibitors also allows enhanced selectivity that iscrucial for decreasing the toxic effects associated with kinaseinhibitors.

The MEK-ERK Pathway is activated in numerous inflammatory conditions(Kyriakis and Avruch, 1996, Vol. 271, No. 40, pp. 24313-24316; Hammakeret al., J. Immunol. 2004, 172, 1612-1618), including rheumatoidarthritis, inflammatory bowel disease and COPD. MEK regulates thebiosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. It hasbeen shown that MEK inhibitors interfere with the production/secretionof these cytokines. Array BioPharma has developed a first-in-class MEKinhibitor (ARRY 438162) and initiated clinical trials in rheumatoidarthritis (RA) patients.

International patent applications WO/2003/053960, WO/2005/023251,WO/2005/121142, WO/2005/051906, WO/2010/121646 describe MEK inhibitors.

BRIEF SUMMARY OF THE INVENTION

The present invention provides anticancer compounds of the generalformula (I), their pharmaceutically acceptable salts, combinations withsuitable medicament and pharmaceutical compositions thereof and usethereof in treating various cancers.

wherein, R¹-R⁵ are described in detail below.

The compounds of the present inventions are potent inhibitors of MEK andshow tumor regression effect with promisingly less side effects.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to heteroaryl compounds of formula I,their pharmaceutically acceptable salts, their combinations withsuitable medicament and pharmaceutical compositions thereof. The presentinvention also includes processes of preparation of the compounds andtheir use in methods of treatment. The compounds are of formula (I)below:

wherein:

R¹ is selected from the group consisting of hydrogen, substituted- orunsubstituted-alkyl, substituted- or unsubstituted-alkenyl, substituted-or unsubstituted-alkynyl, substituted- or unsubstituted-cycloalkyl,substituted- or unsubstituted-cycloalkenyl, substituted- orunsubstituted-aryl, substituted- or unsubstituted-heteroaryl, andsubstituted- or unsubstituted-heterocyclyl;

R² is selected from the group consisting of—(C(R^(c))(R^(d)))_(m)—C(═O)—N(R⁶)R⁷, —C(═O)N(R⁸)R⁹, and—O—(C(R^(c))(R^(d)))_(m)—C(═O)—N(R⁶)R⁷;

R³ is selected from the group consisting of hydrogen, substituted- orunsubstituted-alkyl, and substituted- or unsubstituted-cycloalkyl;

R⁴ is selected from the group consisting of hydrogen, halogen,substituted- or unsubstituted-alkyl, and substituted- orunsubstituted-cycloalkyl;

R⁵ is substituted- or unsubstituted-aryl, wherein the substituents areselected from the group consisting of R^(a) and R^(b);

R⁶ and R⁷ are each independently selected from the group consisting ofhydrogen, substituted- or unsubstituted-alkyl, substituted- orunsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl; or R⁶ and R⁷ taken together with thenitrogen to which they are attached form a substituted- orunsubstituted-heterocyclyl;

R⁸ and R⁹ are each independently selected from the group consisting ofhydrogen, substituted- or unsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl, or R⁸ and R⁹ taken together with thenitrogen to which they are attached form a substituted- orunsubstituted-heterocyclyl;

with the provisos that both R⁸ and R⁹ cannot be hydrogen at the sametime; and when R⁸ and R⁹ are not a part of a heterocycle formed togetherwith the nitrogen to which they are attached, at least one of the R⁸ andR⁹ is substituted- or unsubstituted-cycloalkyl, or substituted- orunsubstituted-heterocyclyl;

R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, halogen and haloalkyl;

R^(c) and R^(d) are independently selected from the group consisting ofhydrogen, halogen, hydroxyl, and substituted- or unsubstituted-alkyl; orR^(c) and R^(d) taken together with the carbon to which they areattached form a substituted- or unsubstituted-cycloalkyl;

m is an integer selected from the group consisting of 1, 2, 3, and 4;

When the alkyl group or alkenyl group is substituted, the alkyl group oralkenyl group is substituted with 1 to 4 substituents independentlyselected from the group consisting of oxo, halogen, nitro, cyano,perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, —SO₂R^(10a),—C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰, —OR^(10b),—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰,—N(alkyl)R¹⁰—N(H)C(═O)N(H)R¹⁰, —N(H)C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl and—NH—SO₂-cycloalkyl.

When the cycloalkyl group or cycloalkenyl group is substituted, thecycloalkyl group or cycloalkenyl group is substituted with 1 to 3substituents independently selected from the group consisting of oxo,halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl, hydroxyalkyl, aryl,heteroaryl, heterocyclyl, —OR^(10b), —SO₂R^(10a), —C(═O)R^(10a),—C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰,—N(H)C(═O)R^(10a), —N(H)R¹⁰, —N(alkyl)R¹⁰, —N(H)C(═O)N(H)R¹⁰, and—N(H)C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl and —NH—SO₂-cycloalkyl.

When the aryl group is substituted, the aryl group is substituted with 1to 3 substituents independently selected from the group consisting ofhalogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl,cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl, —O— perhaloalkyl,—N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl, —SO₂-perhaloalkyl,—N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl, —C(═O)N(alkyl)alkyl,—C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl, —SO₂N(H)alkyl, —SO₂NH₂,—NH—SO₂-alkyl and —NH—SO₂-cycloalkyl.

When the heteroaryl group is substituted, the heteroaryl group issubstituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl,—O-perhaloalkyl, —N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl,—SO₂-perhaloalkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl,—C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl,—SO₂N(H)alkyl, —SO₂NH₂, —NH—SO₂-alkyl and —NH—SO₂-cycloalkyl.

When the heterocyclyl group is substituted, the heterocyclyl group issubstituted with 1 to 3 substituents. When the substituents are on aring carbon of the ‘heterocycle’, the substituents are independentlyselected from the group consisting of halogen, nitro, cyano, oxo, alkyl,alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, —OR^(10b), —C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰,—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰, —N(alkyl)R¹⁰,—N(H)C(═O)N(H)R¹⁰, and —N(H)C(═O)N(alkyl)R¹⁰. When the heterocyclicgroup is substituted on a ring nitrogen of the ‘heterocycle’, thesubstituents are independently selected from the group consisting ofalkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, —SO₂R^(10a),—C(═O)R^(10a), —C(═O)OR^(10a), —C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰,—NH—SO₂-alkyl and —NH—SO₂-cycloalkyl. When the heterocyclic group issubstituted on a ring sulphur of the ‘heterocycle’, is the sulphur issubstituted with 1 or 2 oxo groups.

R¹⁰ is selected from the group consisting of hydrogen, alkyl, alkenyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;

R^(10a) is selected from the group consisting of alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl andheterocyclyl; and

R^(10b) is selected from the group consisting of hydrogen, alkyl,alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl andheterocyclyl.

In certain embodiments, R¹ is selected from the group consisting ofhydrogen, substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-heterocyclyl, andsubstituted- or unsubstituted-cycloalkyl.

In other embodiments, R¹ is selected from the group consisting ofhydrogen, methyl, ethyl, isopropyl, allyl, difluoromethyl, cyclopropyl,3-oxetanyl, —CH₂COOH, —CH₂COOC₂H₅, —CH₂CH(OH)CH₂(OH), and —C₂H₄OH.

In certain embodiments, R³ and R⁴ are substituted- orunsubstituted-alkyl.

In other embodiments, R³ and R⁴ are methyl.

In certain embodiments, R⁵ is substituted- or unsubstituted-phenyl,wherein the substituents are independently selected from R^(a) andR^(b).

In certain embodiments, R^(a) and R^(b) are independently selected fromthe group consisting of hydrogen and halogen.

In other embodiments, R^(a) and R^(b) are independently fluorine oriodine.

In certain embodiments, R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen, substituted- or unsubstituted-alkyl,halogen, and hydroxyl, or R^(c) and R^(d) taken together with the carbonto which they are attached form a substituted- orunsubstituted-cycloalkyl ring.

In other embodiments, R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen, methyl, fluoro and hydroxyl; or R^(c)and R^(d) taken together with the carbon to which they are attached forma cyclopropyl ring.

In certain embodiments, m is 1 or 2.

In certain embodiments, R⁶ and R⁷ are independently selected from thegroup consisting of hydrogen, substituted- or unsubstituted-alkyl,substituted- or unsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl; or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached form a substituted- orunsubstituted-heterocycle.

In other embodiments, R⁶ and R⁷ are independently selected from thegroup consisting of hydrogen, methyl, cyclopropyl, and 3-oxetane; or R⁶and R⁷ taken together with the nitrogen atom to which they are attachedform azetidinyl or 3-hydroxyazetidinyl.

In certain embodiments, R⁸ and R⁹ are independently selected from thegroup consisting of hydrogen, substituted- or unsubstituted-cycloalkyland substituted- or unsubstituted-heterocyclyl, or R⁸ and R⁹ takentogether with the nitrogen to which they are attached form asubstituted- or unsubstituted-heterocycle; with the provisos that bothR⁸ and R⁹ are not hydrogen at the same time, and when R⁸ and R⁹ are nota part of a heterocycle formed together with the nitrogen to which theyare attached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl.

In other embodiments, R⁸ and R⁹ are independently selected from thegroup consisting of hydrogen, cyclopropyl, cyclopropyl substituted with—C(═O)NH₂ or —CH₂OH, 3-oxetanyl, tetrahydrofuran-3-yl, andtetrahydro-2H-pyranyl, or R⁸ and R⁹ together with the nitrogen to whichthey are attached form 1,1-dioxidothiazolidinyl,1,1-dioxidothiomorpholinyl, morpholinyl, azetidinyl, 1-pyrrolidinyl,piperazinyl, 4-methylpiperazinyl, 3-hydroxypyrrolidinyl or4-hydroxypiperidinyl; with the provisos that both R⁸ and R⁹ are nothydrogen at the same time, and when R⁸ and R⁹ are not a part of aheterocycle formed together with the nitrogen to which they areattached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl.

In one embodiment, the present invention is a compound of formula Ia:

wherein:

R¹, R³, R⁴, R⁶, R⁷, R^(a), R^(b), R^(c), R^(d) and ‘m’ are as defined informula (I).

In another embodiment, the present invention is a compound of formula(Ib):

wherein:

R¹, R³, R⁴, R⁸, R⁹, R^(a) and R^(b) are as defined in formula (I); withthe provisos that both R⁸ and R⁹ cannot be hydrogen at the same time,and at least one of the R⁸ and R⁹ is selected from the group consistingof substituted- or unsubstituted-aryl, substituted- orunsubstituted-cycloalkyl, substituted- or unsubstituted-cycloalkenyl,substituted- or unsubstituted-heterocyclyl; or R⁸ and R⁹ taken togetherwith the nitrogen to which they are attached form a substituted- orunsubstituted-heterocycle.

In another embodiment, the present invention is a compound of formula(Ic):

wherein: R¹, R³, R⁴, R⁶, R⁷, R^(a), R^(b), R^(c), R^(d) and ‘m’ are asdefined in formula (I).

General terms used in any of the formulae herein can be defined asfollows; however, the meaning stated should not be interpreted aslimiting the scope of the term per se.

The term “alkyl”, as used herein, means a straight or branchedhydrocarbyl chain containing from 1 to 20 carbon atoms. Preferably, thealkyl group contains 1 to 10 carbon atoms. More preferably, alkyl groupcontains up to 6 carbon atoms. Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

The term “alkenyl” as used herein, means an ‘alkyl’ group as definedhereinabove containing 2 to 20 carbon atoms and containing at least onedouble bond. Representative examples of alkenyl include, but are notlimited to, pent-2-enyl, hex-3-enyl, allyl, vinyl, and the like.

When the alkyl or alkenyl groups are substituted alkyl or substitutedalkenyl groups, the alkyl or alkenyl groups are substituted with 1 to 4substituents selected independently from the group consisting of oxo,halogen, nitro, cyano, haloalkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, —OR^(10b), —SO₂R^(10a), —C(═O)R^(10a), —C(═O)OR^(10a),—OC(═O)R^(10a), —C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a),—N(H)R¹⁰, —N(alkyl)R¹⁰, —N(H)C(═O)N(H)R¹⁰, —N(H)C(═O)N(alkyl)R¹⁰,—NH—SO₂-alkyl and —NH—SO₂-cycloalkyl; wherein, R¹⁰ is selected from thegroup consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, and heterocyclyl; R^(10a) is selected from the groupconsisting of alkyl, alkenyl, haloalkyl, perhaloalkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, heterocyclyl; R^(10b) is selected fromthe group consisting of hydrogen, alkyl, alkenyl, haloalkyl,perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl.

The term “haloalkyl” means alkyl, as the case may be, substituted withone or more halogen atoms, where alkyl groups are as defined above. Theterm “halo” is used herein interchangeably with the term “halogen” andmeans F, Cl, Br or I. Examples of “haloalkyl” include but are notlimited to trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, pentachloroethyl, 4,4,4-trifluorobutyl,4,4-difluorocyclohexyl, chloromethyl, dichloromethyl, trichloromethyl,1-bromoethyl and the like. The term “perhaloalkyl” group is definedhereinabove wherein all the hydrogen atoms of the said alkyl group aresubstituted with halogen, exemplified by trifluoromethyl,pentafluoroethyl and the like.

The term “hydroxyalkyl” means alkyl, as the case may be, substitutedwith one or more hydroxyl group(s), where alkyl groups are as definedabove. The term “hydroxy” as used herein means “—OH”. Examples of“hydroxyalkyl” include but are not limited to —CH₂OH, —CH₂CH₂OH,—CH(OH)CH₂OH and the like.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, ortricyclic non-aromatic ring system containing from 3 to 14 carbon atoms,preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ringsystems include monocyclic ring system fused across a bond with anothercyclic system which may be an alicyclic ring or an aromatic ring.Bicyclic rings also include spirocyclic systems wherein the second ringgets annulated on a single carbon atom. Bicyclic ring systems are alsoexemplified by a bridged monocyclic ring system in which twonon-adjacent carbon atoms of the monocyclic ring are linked by analkylene bridge. Examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane,bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene,spiro[2.5]octane, spiro[4.5]decane,spiro[bicyclo[4.1.0]heptane-2,1′-cyclopentane],hexahydro-2′H-spiro[cyclopropane-1,1′-pentalene]. Tricyclic ring systemsare the systems wherein the bicyclic systems as described about arefurther annulated with third ring, which may be alicyclic ring oraromatic ring. Tricyclic ring systems are also exemplified by a bicyclicring system in which two non-adjacent carbon atoms of the bicyclic ringare linked by a bond or an alkylene bridge. Examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0.^(3.7)]nonaneand tricyclo[3.3.1.1^(3.7)]decane (adamantane).

The term “cycloalkenyl” as used herein, means a cycloalkyl group asdefined above containing at least one double bond.

When the cycloalkyl or cycloalkenyl groups are substituted cycloalkyl orsubstituted cycloalkenyl groups, the cycloalkyl and cycloalkenyl groupsare substituted with 1 to 3 substituents selected independently from thegroup consisting of oxo, halogen, nitro, cyano, hydroxyl, hydroxyalkyl,alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, —OR^(10b),—SO₂R^(10a), —C(═O)R^(10a), —C(═O)OR^(10a), —OC(═O)R^(10a),—C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰,—N(alkyl)R¹⁰, —N(H)C(═O)N(H)R¹⁰, —N(H)C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyland —NH—SO₂-cycloalkyl; wherein, R¹⁰ is selected from the groupconsisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, and heterocyclyl; R^(10a) is selected from the groupconsisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocyclyl; R^(10b) is selected from the groupconsisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl,cycloalkenyl, aryl, heteroaryl, and heterocyclyl.

The term “aryl” refers to a monocyclic, bicyclic or tricyclic aromatichydrocarbon ring system. Examples of aryl groups include phenyl,naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Arylgroup also includes partially saturated bicyclic and tricyclic aromatichydrocarbons such as tetrahydro-naphthalene.

When the aryl group is a substituted aryl group, the aryl group issubstituted with 1 to 3 substituents selected independently from thegroup consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl, —O—perhaloalkyl, —N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl,—SO₂-perhaloalkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl,—C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl,—SO₂N(H)alkyl, —SO₂NH₂, —NH—SO₂-alkyl and —NH—SO₂-cycloalkyl;

The term “heteroaryl” refers to a 5-14 membered monocyclic, bicyclic, ortricyclic ring system having 1-4 ring heteroatoms selected from O, N, orS, and the remainder ring atoms being carbon (with appropriate hydrogenatoms unless otherwise indicated), wherein at least one ring in the ringsystem is aromatic. Heteroaryl groups may be optionally substituted withone or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms ofeach ring of a heteroaryl group may be substituted by a substituent.Examples of heteroaryl groups include, but not limited to pyridyl,1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl,imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl,isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl,tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, andbenzo(b)thienyl, 2,3-thiadiazolyl, 1H-pyrazolo[5,1-c]-1,2,4-triazolyl,pyrrolo[3,4-d]-1,2,3-triazolyl, cyclopentatriazolyl,3H-pyrrolo[3,4-c]isoxazolyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,2,3-dihydro-benzo[1,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl,2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl,2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-1H-indol-5-yl,2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl,2,3-dihydro-1H-indol-7-yl, benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.

When the heteroaryl group is a substituted heteroaryl group, theheteroaryl group is substituted with 1 to 3 substituents selected fromthe group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl,O-perhaloalkyl, —N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl,—SO₂-perhaloalkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl,—C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl,—SO₂N(H)alkyl, —SO₂NH₂, —NH—SO₂-alkyl and —NH—SO₂-cycloalkyl.

The term “heterocycle” or “heterocyclic” as used herein, means a‘cycloalkyl’ group wherein one or more of the carbon atoms replaced by—O—, —S—, —S(O₂)—, —S(O)—, —N(R^(m))—, —Si(R^(m))R^(n)—, wherein, R^(m)and R^(n) are independently selected from the group consisting ofhydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl. Theheterocycle may be connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the heterocycle.Examples of monocyclic heterocycle include, but are not limited to,azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl,1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl,oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1.1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. Examples ofbicyclic heterocycle include, but are not limited to 1,3-benzodioxolyl,1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The termheterocycle also include bridged heterocyclic systems such asazabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane and the like.

When the heterocyclic group is substituted, it may be substituted eitheron a ring carbon atom or on a ring hetero atom. When it substituted on aring carbon atom, it is substituted with 1-3 substituents independentlyselected from the group consisting of halogen, nitro, cyano, oxo, alkyl,alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, —OR^(10b), —C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰,—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰, —N(alkyl)R¹⁰,—N(H)C(═O)N(H)R¹⁰, and —N(H)C(═O)N(alkyl)R¹⁰. When the ‘heterocyclic’group is substituted on a ring nitrogen, it is substituted with asubstituent selected from the group consisting of alkyl, alkenyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, —SO₂R^(10a), —C(═O)R^(10a),—C(═O)OR^(10a), —C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl and—NH—SO₂-cycloalkyl. When the heterocyclic group is substituted on a ringsulphur of ‘heterocycle’, it is substituted with 1 or 2 oxo group.

The term ‘oxo’ means a divalent oxygen (═O) attached to the parentgroup. For example oxo attached to carbon forms a carbonyl, oxosubstituted on cyclohexane forms a cyclohexanone, and the like.

The term ‘annulated’ means the ring system under consideration is eitherannulated with another ring at a carbon atom of the cyclic system oracross a bond of the cyclic system as in the case of fused or spiro ringsystems.

The term ‘bridged’ means the ring system under consideration contain analkylene bridge having 1 to 4 methylene units joining two non adjacentring atoms.

It should be understood that the formulas (I), (Ia), (Ib) and (Ic)structurally encompasses all stereoisomers, tautomers andpharmaceutically acceptable salts that may be contemplated from thechemical structure of the genera described herein.

A compound, its stereoisomers, racemates, tautomers and pharmaceuticallyacceptable salt thereof as described hereinabove wherein the compound ofgeneral formula I, (Ia), (Ib) and (Ic) can be selected from the groupconsisting of:

-   3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 1)-   N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 2)-   1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 3)-   N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 4)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide (Compound    5)-   N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 6)-   5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 7)-   1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 8)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide    (Compound 9)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide    (Compound 10)-   2,2-difluoro-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 11)-   N-(1-carbamoylcyclopropyl)-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 12)-   3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide    (Compound 13)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound    14)-   3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide    (Compound 15)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 16)-   1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 17)-   5-((2-fluoro-4-iodophenyl)amino)-1-(3-(4-hydroxypiperidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 18)-   N-cyclopropyl-3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 19)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-2-methylpropanamide    (Compound 20)-   5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(4-methylpiperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 21)-   5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 22)-   5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 23)-   1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 24)-   N-cyclopropyl-2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,    6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 25)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 26)-   3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(pyrrolidine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 27)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide    (Compound 28)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide    (Compound 29)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,7,8-tetrahydropyrido[2,3-d]pyrimidin-1(2H)-yl)phenyl)-2,2-difluoroacetamide    (Compound 30)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,    7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide    (Compound 31)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide    (Compound 32)-   3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxo    ethyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 33)-   3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 34)-   2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 35)-   3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,    7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide    (Compound 36)-   N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 37)-   3-cyclopropyl-1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 38)-   3-cyclopropyl-1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 39)-   N-cyclopropyl-3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 40)-   N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 41)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 42)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra    hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide    (Compound 43)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra    hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide    (Compound 44)-   2,2-difluoro-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 45)-   1-(3-(2-(azetidin-1-yl)-2-oxoethyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 46)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound    47)-   5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 48)-   3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetra    hydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(oxetan-3-yl)benzamide    (Compound 49)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide    (Compound 50)-   3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydrofuran-3-yl)benzamide    (Compound 51)-   3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide    (Compound 52)-   3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(1-(hydroxymethyl)cyclopropyl)benzamide    (Compound 53)-   N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,    7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 54)-   N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-(2-hydroxyethyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 55)-   1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 56)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 57)-   N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 58)-   N-cyclopropyl-2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide    (Compound 59)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide    (Compound 60)-   3-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 61)-   N-cyclopropyl-3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,    7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 62)-   5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-1-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 63)-   ethyl    2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3    (4H)-yl)acetate (Compound 64)-   1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 65)-   1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione    (Compound 66)-   2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide    (Compound 67)-   3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide    (Compound 68)-   N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-isopropyl-6,8-dimethyl-2,4,7-trioxo-3,4,6,    7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 69)-   3-(3-allyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-cyclopropylbenzamide    (Compound 70)-   2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-3-(oxetan-3-yl)-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide    (Compound 71)-   N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 72)-   N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide    (Compound 73)-   2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetic    acid (Compound 74)-   (R)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide    (Compound 75)-   (S)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide    (Compound 76)-   1-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-2,4,7-trioxo-3,4,6,7-tetra    hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide    (Compound 77)-   1-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetra    hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide    (Compound 78) and-   1-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro    pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide    (Compound 79)

The present disclosure provides a method for inhibiting MEK enzymescomprising contacting said MEK enzyme with a composition comprising acompound of I, Ia, Ib, Ic, their tautomeric forms, their stereoisomersor their pharmaceutically acceptable salts, sufficient to inhibit saidenzyme, wherein said enzyme inhibited MEK kinase, which occurs withincell.

The invention also provides a method of treatment of a MEK mediateddisorder in an individual suffering from said disorder, comprisingadministering to said individual an effective amount of a compositioncomprising a compound of formula I, Ia, Ib, Ic, their tautomeric forms,their stereoisomers or their pharmaceutically acceptable salts. Themethod of treatment may also be combined with an additional therapy suchas radiation therapy, chemotherapy, or combination thereof.

MEK mediated disorders, as stated above, include inflammatory diseases,infections, autoimmune disorders, stroke, ischemia, cardiac disorder,neurological disorders, fibrogenetic disorders, proliferative disorders,hyperproliferative disorders, tumors, leukemias, neoplasms, cancers,carcinomas, metabolic diseases and malignant diseases.

The invention further provides a method for the treatment or prophylaxisof a proliferative disease in an individual comprising administering tosaid individual an effective amount of a composition comprising acompound of formula I, Ia, Ib, Ic, their tautomeric forms, theirstereoisomers or their pharmaceutically acceptable salts. Theproliferative disease includes cancer, psoriasis, restenosis, autoimmunedisease, or atherosclerosis.

The invention also provides a method for the treatment or prophylaxis ofan inflammatory disease in an individual comprising administering tosaid individual an effective amount of a composition comprising acompound of formula I, Ia, Ib, Ic, their tautomeric forms, theirstereoisomers or their pharmaceutically acceptable salts. Theinflammatory disease includes rheumatoid arthritis or multiplesclerosis.

The invention also provide a method for degrading, inhibiting the growthof or killing cancer cells comprising contacting the cells with anamount of a composition effective to degrade, inhibit the growth of orkill cancer cells, the composition comprising a compound of formula I,Ia, Ib, Ic, their tautomeric forms, their stereoisomers or theirpharmaceutically acceptable salts.

The invention also provide a method of inhibiting tumor size increase,reducing the size of a tumor, reducing tumor proliferation or preventingtumor proliferation in an individual in need thereof comprisingadministering to said individual an effective amount of a composition toinhibit tumor size increase, reduce the size of a tumor, reduce tumorproliferation or prevent tumor proliferation, the composition comprisinga compound of formula I, Ia, Ib, Ic, their tautomeric forms, theirstereoisomers or their pharmaceutically acceptable salts.

The MEK-ERK pathway is activated in numerous inflammatory conditions(Kyriakis and Avruch 1996, Vol. 271, No. 40, pp. 24313-24316; Hammakeret al., J Immunol 2004; 172; 1612-1618), including rheumatoid arthritis,inflammatory bowel disease and COPD.

The present invention describes the inhibitors of MEK kinase fortreatment of disorders that are driven by hyperactivation, abnormalactivation, constitutive activation, gain-of-function mutation of theMEK kinase and/or its substrate kinases that include but are not limitedto ERK. Such disorders encompass hyperproliferative disorders thatinclude but are not limited to psoriasis, keloids, hyperplasia of theskin, benign prostatic hyperplasia (BPH), solid tumors such as cancersof the respiratory tract (including but not limited to small cell andnon-small cell lung carcinomas), brain (including but not limited toglioma, medulloblastoma, ependymoma, neuroectodermal and pineal tumors),breast (including but not limited to invasive ductal carcinoma, invasivelobular carcinoma, ductal- and lobular carcinoma in situ), reproductiveorgans (including but not limited to prostate cancer, testicular cancer,ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer,vulvar cancer, and sarcoma of the uterus), digestive tract (includingbut not limited to esophageal, colon, colorectal, gastric, gall blabber,pancreatic, rectal, anal, small intestine and salivary gland cancers),urinary tract (including but not limited to bladder, ureter, kidney,renal, urethral and papillary renal cancers), eye (including but notlimited to intraocular melanoma, and retinoblastoma), liver (includingbut not limited to hepatocellular carcinoma, and cholangiocarcinoma),skin (including but not limited to melanoma, squamous cell carcinoma,Kaposi's sarcoma, Merkel cell skin cancer, non-melanoma skin cancer),head and neck (including but not limited to laryngeal, nasopharyngeal,hypopharyngeal, oropharyngeal cancer, lip and oral cavity cancer andsquamous cell cancer), thyroid, parathyroid, and their metastases. Thehyperrproliferative disorders also include, leukemias (including but notlimited to acute lymphoblastic leukemia, acute myeloid leukemia, chronicmelogenous leukemia, chronic lymphocytic leukemia, and hairy cellleukemia), sarcomas (including but not limited to soft tissue sarcoma,osteosarcoma, lymphosarcoma, rhabdomyosarcoma), and lymphomas (includingbut not limited to non-Hodgkin's lymphoma, AIDS-related lymphoma,cutaneous T cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, andlymphoma of the central nervous system).

The present invention describes the inhibitors of MEK kinase fortreatment of certain disorders involving aberrant regulation of themitogen extracellular kinase activity including but not limited tohepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer'sdisease, cystic fibrosis, septic shock or asthma.

The present invention describes the inhibitors of MEK kinase fortreatment of diseases and disorders associated with aberrant, abnormaland/or excessive angiogenesis. Such disorders associated withangiogenesis include but are not limited to, tumor growth andmetastases, ischemic retinal vein occlusion, diabetic retinopathy,macular degeneration, neovascular glaucoma, psoriasis, inflammation,rheumatoid arthritis, vascular graft restenosis, restenosis and in-stentrestenosis.

The compounds mentioned in this invention can be used as a single (sole)therapeutic agent or in combination with other active agents, includingchemotherapeutic agents and anti-inflammatory agents. Such combinationsinclude but are not limited to combining the MEK kinase inhibitors withanti-mitotic agents, anti-antiangiogenic agents, alkylating agents,anti-hyperproliferative agents, antimetabolites, DNA-intercalatingagents, cell cycle inhibitors, kinase inhibitors, growth factorinhibitors, enzyme inhibitors, topoisomerase inhibitors, biologicalresponse modifiers or anti-hormones.

The term ‘room temperature’ denotes any temperature ranging betweenabout 20° C. to about 40° C., except and otherwise it is specificallymentioned in the specification.

The intermediates and the compounds of the present invention may beobtained in pure form in a manner known per se, for example, bydistilling off the solvent in vacuum and re-crystallizing the residueobtained from a suitable solvent, such as pentane, diethyl ether,isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone ortheir combinations or subjecting it to one of the purification methods,such as column chromatography (e.g., flash chromatography) on a suitablesupport material such as alumina or silica gel using eluent such asdichloromethane, ethyl acetate, hexane, methanol, acetone and theircombinations. Preparative LC-MS method is also used for the purificationof molecules described herein.

Salts of compound of formula I can be obtained by dissolving thecompound in a suitable solvent, for example in a chlorinatedhydrocarbon, such as methyl chloride or chloroform or a low molecularweight aliphatic alcohol, for example, ethanol or isopropanol, which wasthen treated with the desired acid or base as described in Berge S. M.et al. “Pharmaceutical Salts, a review article in Journal ofPharmaceutical sciences volume 66, page 1-19 (1977)” and in handbook ofpharmaceutical salts properties, selection, and use by P. H. EinrichStahland Camille G. wermuth, Wiley—VCH (2002). Lists of suitable saltscan also be found in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, p. 1445, and Journal ofPharmaceutical Science, 66, 2-19 (1977). For example, the salt can be ofan alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g.,calcium), or ammonium.

The compound of the invention or a composition thereof can potentiallybe administered as a pharmaceutically acceptable acid-addition, baseneutralized or addition salt, formed by reaction with inorganic acids,such as hydrochloric acid, hydrobromic acid, perchloric acid, nitricacid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organicacids such as formic acid, acetic acid, propionic acid, glycolic acid,lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid,maleic acid, and fumaric acid, or by reaction with an inorganic base,such as sodium hydroxide, potassium hydroxide. The conversion to a saltis accomplished by treatment of the base compound with at least astoichiometric amount of an appropriate acid. Typically, the free baseis dissolved in an inert organic solvent such as diethyl ether, ethylacetate, chloroform, ethanol, methanol, and the like, and the acid isadded in a similar solvent. The mixture is maintained at a suitabletemperature (e.g., between 0° C. and 50° C.). The resulting saltprecipitates spontaneously or can be brought out of solution with a lesspolar solvent.

The stereoisomers of the compounds of formula I of the present inventionmay be prepared by stereospecific syntheses or resolution of racemiccompound using an optically active amine, acid or complex forming agent,and separating the diastereomeric salt/complex by fractionalcrystallization or by column chromatography.

The compounds of formula I of the present invention can exist intautomeric forms, such as keto-enol tautomers. Such tautomeric forms arecontemplated as an objective of this invention and such tautomers may bein equilibrium or predominant in one of the forms.

The prodrugs can be prepared in situ during the isolation andpurification of the compounds, or by separately reacting the purifiedcompound with a suitable derivatizing agent. For example, hydroxy groupscan be converted into esters via treatment with a carboxylic acid in thepresence of a catalyst. Examples of cleavable alcohol prodrug moietiesinclude substituted or unsubstituted, branched or unbranched lower alkylester moieties, e.g., ethyl esters, lower alkenyl esters, di-loweralkylamino lower-alkyl esters, e.g., dimethylaminoethyl ester, acylaminolower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethylester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g.,benzyl ester, substituted- or unsubstituted, e.g., with methyl, halo, ormethoxy substituents aryl and aryl-lower alkyl esters, amides,lower-alkyl amides, di-lower alkyl amides, and hydroxy amides.

The term “prodrug” denotes a derivative of a compound, which derivative,when administered to warm-blooded animals, e.g. humans, is convertedinto the compound (drug). The enzymatic and/or chemical hydrolyticcleavage of the compounds of the present invention occurs in such amanner that the proven drug form (parent carboxylic acid drug) isreleased, and the moiety or moieties split off remain nontoxic or aremetabolized so that nontoxic metabolic products are produced. Forexample, a carboxylic acid group can be esterified, e.g., with a methylgroup or ethyl group to yield an ester. When an ester is administered toa subject, the ester is cleaved, enzymatically or non-enzymatically,reductively, oxidatively, or hydrolytically, to reveal the anionicgroup. An anionic group can be esterified with moieties (e.g.,acyloxymethyl esters) which are cleaved to reveal an intermediatecompound which subsequently decomposes to yield the active compound.

The inhibitors mentioned in the present invention can be combined withanti-inflammatory agents or agents that show therapeutic benefit forconditions including but not limited to hepatomegaly, heart failure,cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis,septic shock or asthma, diabetic retinopathy, ischemic retinal veinocclusion, macular degeneration, neovascular glaucoma, psoriasis,inflammation, rheumatoid arthritis, restenosis, in-stent restenosis, andvascular graft restenosis.

The term “aberrant kinase activity” refers to any abnormal expression oractivity of the gene encoding the kinase or of the polypeptide itencodes. Examples of such aberrant kinase activity include but are notlimited to over-expression of the gene or polypeptide, geneamplification, mutations that produce constitutively active orhyperactive kinase activity, gene mutations, deletions, substitutions,additions, and the like.

Thus the present invention further provides a pharmaceuticalcomposition, containing the compounds of the general formula (I) asdefined above, its tautomeric forms, its stereoisomers, itspharmaceutically acceptable salts in combination with the usualpharmaceutically acceptable carriers, diluents, excipients, and thelike.

The pharmaceutically acceptable carrier or excipient is preferably onethat is chemically inert to the compound of the invention and one thathas no detrimental side effects or toxicity under the conditions of use.Such pharmaceutically acceptable carriers or excipients include saline(e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oiland ethylene oxide available from Sigma Chemical Co., St. Louis, Mo.)(e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90%saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g., 40%propylene glycol/10% ethanol/50% water), polyethylene glycol (e.g., 40%PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). Apreferred pharmaceutical carrier is polyethylene glycol, such as PEG400, and particularly a composition comprising 40% PEG 400 and 60% wateror saline. The choice of carrier will be determined in part by theparticular compound chosen, as well as by the particular method used toadminister the composition. Accordingly, there is a wide variety ofsuitable formulations of the pharmaceutical composition of the presentinvention.

The following formulations for oral, aerosol, parenteral, subcutaneous,intravenous, intraarterial, intramuscular, interperitoneal, rectal, andvaginal administration are merely exemplary and are in no way limiting.

The pharmaceutical compositions can be administered parenterally, e.g.,intravenously, intraarterially, subcutaneously, intradermally,intrathecally, or intramuscularly. Thus, the invention providescompositions for parenteral administration that comprise a solution ofthe compound of the invention dissolved or suspended in an acceptablecarrier suitable for parenteral administration, including aqueous andnon-aqueous, isotonic sterile injection solutions.

Overall, the requirements for effective pharmaceutical carriers forparenteral compositions are well known to those of ordinary skill in theart. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Company,Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), andASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630(1986). Such compositions include solutions containing anti-oxidants,buffers, bacteriostats, and solutes that render the formulation isotonicwith the blood of the intended recipient, and aqueous and non-aqueoussterile suspensions that can include suspending agents, solubilizers,thickening agents, stabilizers, and preservatives. The compound can beadministered in a physiologically acceptable diluent in a pharmaceuticalcarrier, such as a sterile liquid or mixture of liquids, includingwater, saline, aqueous dextrose and related sugar solutions, an alcohol,such as ethanol, isopropanol (for example in topical applications), orhexadecyl alcohol, glycols, such as propylene glycol or polyethyleneglycol, dimethylsulfoxide, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such aspoly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride, with or without theaddition of a pharmaceutically acceptable surfactant, such as a soap ora detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils useful in parenteral formulations include petroleum, animal,vegetable, and synthetic oils. Specific examples of oils useful in suchformulations include peanut, soybean, sesame, cottonseed, corn, olive,petrolatum, and mineral oil. Suitable fatty acids for use in parenteralformulations include oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acidesters.

Suitable soaps for use in parenteral formulations include fatty alkalimetal, ammonium, and triethanolamine salts, and suitable detergentsinclude (a) cationic detergents such as, for example, dimethyl dialkylammonium halides, and alkyl pyridinium halides, (b) anionic detergentssuch as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin,ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionicdetergents such as, for example, fatty amine oxides, fatty acidalkanolamides, and polyoxyethylene polypropylene copolymers, (d)amphoteric detergents such as, for example, alkyl-β-aminopropionates,and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixturesthereof.

The parenteral formulations typically will contain from about 0.5% orless to about 25% or more by weight of a compound of the invention insolution. Preservatives and buffers can be used. In order to minimize oreliminate irritation at the site of injection, such compositions cancontain one or more nonionic surfactants having a hydrophile-lipophilebalance (HLB) of from about 12 to about 17. The quantity of surfactantin such formulations will typically range from about 5% to about 15% byweight. Suitable surfactants include polyethylene sorbitan fatty acidesters, such as sorbitan monooleate and the high molecular weightadducts of ethylene oxide with a hydrophobic base, formed by thecondensation of propylene oxide with propylene glycol. The parenteralformulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid excipient, for example, water, for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions can be prepared from sterile powders, granules, and tablets.

Topical formulations, including those that are useful for transdermaldrug release, are well known to those of skill in the art and aresuitable in the context of the present invention for application toskin.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of a compound of the inventiondissolved in diluents, such as water, saline, or orange juice; (b)capsules, sachets, tablets, lozenges, and troches, each containing apre-determined amount of the compound of the invention, as solids orgranules; (c) powders; (d) suspensions in an appropriate liquid; and (e)suitable emulsions. Liquid formulations can include diluents, such aswater and alcohols, for example, ethanol, benzyl alcohol, and thepolyethylene alcohols, either with or without the addition of apharmaceutically acceptable surfactant, suspending agent, or emulsifyingagent. Capsule forms can be of the ordinary hard- or soft-shelledgelatin type containing, for example, surfactants, lubricants, and inertfillers, such as lactose, sucrose, calcium phosphate, and cornstarch.Tablet forms can include one or more of lactose, sucrose, mannitol, cornstarch, potato starch, alginic acid, microcrystalline cellulose, acacia,gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium,talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid,and other excipients, colorants, diluents, buffering agents,disintegrating agents, moistening agents, preservatives, flavoringagents, and pharmacologically compatible excipients. Lozenge forms cancomprise the compound ingredient in a flavor, usually sucrose and acaciaor tragacanth, as well as pastilles comprising a compound of theinvention in an inert base, such as gelatin and glycerin, or sucrose andacacia, emulsions, gels, and the like containing, in addition to thecompound of the invention, such excipients as are known in the art.

A compound of the present invention, alone or in combination with othersuitable components, can be made into aerosol formulations to beadministered via inhalation. A compound or epimer of the invention ispreferably supplied in finely divided form along with a surfactant andpropellant. Typical percentages of the compounds of the invention can beabout 0.01% to about 20% by weight, preferably about 1% to about 10% byweight. The surfactant must, of course, be nontoxic, and preferablysoluble in the propellant. Representative of such surfactants are theesters or partial esters of fatty acids containing from 6 to 22 carbonatoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic,linolenic, olesteric and oleic acids with an aliphatic polyhydricalcohol or its cyclic anhydride. Mixed esters, such as mixed or naturalglycerides can be employed. The surfactant can constitute from about0.1% to about 20% by weight of the composition, preferably from about0.25% to about 5%. The balance of the composition is ordinarilypropellant. A carrier can also be included as desired, e.g., lecithin,for intranasal delivery. These aerosol formulations can be placed intoacceptable pressurized propellants, such as dichlorodifluoromethane,propane, nitrogen, and the like. They also can be formulated aspharmaceuticals for non-pressured preparations, such as in a nebulizeror an atomizer. Such spray formulations can be used to spray mucosa.

Additionally, the compound of the invention can be made intosuppositories by mixing with a variety of bases, such as emulsifyingbases or water-soluble bases. Formulations suitable for vaginaladministration can be presented as pessaries, tampons, creams, gels,pastes, foams, or spray formulas containing, in addition to the compoundingredient, such carriers as are known in the art to be appropriate.

The concentration of the compound in the pharmaceutical formulations canvary, e.g., from less than about 1% to about 10%, to as much as about20% to about 50% or more by weight, and can be selected primarily byfluid volumes, and viscosities, in accordance with the particular modeof administration selected.

For example, a typical pharmaceutical composition for intravenousinfusion could be made up to contain 250 ml of sterile Ringer'ssolution, and 100 mg of at least one compound of the invention. Actualmethods for preparing parenterally administrable compounds of theinvention will be known or apparent to those skilled in the art and aredescribed in more detail in, for example, Remington's PharmaceuticalScience (17^(th) ed., Mack Publishing Company, Easton, Pa., 1985).

It will be appreciated by one of ordinary skill in the art that, inaddition to the aforedescribed pharmaceutical compositions, the compoundof the invention can be formulated as inclusion complexes, such ascyclodextrin inclusion complexes, or liposomes. Liposomes can serve totarget a compound of the invention to a particular tissue, such aslymphoid tissue or cancerous hepatic cells. Liposomes can also be usedto increase the half-life of a compound of the invention. Many methodsare available for preparing liposomes, as described in, for example,Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Pat.Nos. 4,235,871, 4,501,728, 4,837,028, and 5,019,369.

The compounds of the invention can be administered in a dose sufficientto treat the disease, condition or disorder. Such doses are known in theart (see, for example, the Physicians' Desk Reference (2004)). Thecompounds can be administered using techniques such as those describedin, for example, Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) andPhysicians' Desk Reference, 58th ed., Thomson PDR (2004).

Suitable doses and dosage regimens can be determined by conventionalrange-finding techniques known to those of ordinary skill in the art.Generally, treatment is initiated with smaller dosages that are lessthan the optimum dose of the compound of the present invention.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. The present methodcan involve the administration of about 0.1 μg to about 50 mg of atleast one compound of the invention per kg body weight of theindividual. For a 70 kg patient, dosages of from about 10 μg to about200 mg of the compound of the invention would be more commonly used,depending on a patient's physiological response.

By way of example and not intending to limit the invention, the dose ofthe pharmaceutically active agent(s) described herein for methods oftreating or preventing a disease or condition as described above can beabout 0.001 to about 1 mg/kg body weight of the subject per day, forexample, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5mg, 0.75 mg, or 1 mg/kg body weight per day. The dose of thepharmaceutically active agent(s) described herein for the describedmethods can be about 1 to about 1000 mg/kg body weight of the subjectbeing treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500mg, 750 mg, or 1000 mg/kg body weight per day.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, thedisclosed methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10%. Furthermore, the treatment, prevention, amelioration, orinhibition provided by the inventive method can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder, e.g., cancer. Also, for purposes herein,“treatment,” “prevention,” “amelioration,” or “inhibition” can encompassdelaying the onset of the disorder, or a symptom or condition thereof.

In accordance with the invention, the term subject includes an “animal”which in turn includes a mammal such as, without limitation, the orderRodentia, such as mice, and the order Lagomorpha, such as rabbits. Inone aspect, the mammals are from the order Carnivora, including Felines(cats) and Canines (dogs). In another aspect, the mammals are from theorder Artiodactyla, including Bovines (cows) and Swine (pigs) or of theorder Perssodactyla, including Equines (horses). In a further aspect,the mammals are of the order Primates, Ceboids, or Simoids (monkeys) orof the order Anthropoids (humans and apes). In yet another aspect, themammal is human.

General Method of Preparation

The compounds of general formula (I) where all the symbols are asdefined earlier can be prepared by methods given in below schemes orexamples illustrated herein below.

However, the disclosure should not be construed to limit the scope ofthe invention arriving at compound of formula (I) disclosed hereinabove.

Scheme 1 (R¹ is H)

Compound of formula (I) where R¹ is H, can be prepared as depicted inScheme 1, details of which are given below.

Step-1

Compound of formula (II) where R¹ is N-protecting group, can beconverted to compound of formula (III) by reacting compound of (II)(Prepared as per reference WO2005121142) (Z is any suitable leavinggroup like Cl, Br, I, —O(SO)₂(4-MePh), —O(SO)₂CH₃, —O(SO)₂CF₃ etc.) withR²NH₂ in presence of a suitable base like 2,6-Lutidine,1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂CO₃, Cs₂CO₃, NaH, KH,n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solventlike THF, DMF, DMSO etc., at temperature ranging from about −78° C. toabout 150° C.

Step-2

Compound of formula-(III) where R¹ is N-protecting group, can beconverted to compound of formula-(IV) by reacting compound of formula(III) with suitable base such as NaOMe, K₂CO₃ etc. in a solvent likeMethanol, Ethanol, THF, DMF etc. at temperature ranging from about −78°C. to about 150° C.

Step-3

Compound of formula-(IV) where R¹ is N-protecting group, can beconverted to compound of formula-(I) by reacting compound of formula(IV) with suitable N-deprotection agents such as AlCl₃, Pd—C/H₂ etc. ina solvent like Anisole, Toluene, Xylene, THF, DMF, DMSO etc. attemperature ranging from about −78° C. to about 150° C.

Scheme-2:

Compound of formula (I), where R¹ is selected from the group consistingof substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-alkynyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl, can be prepared as depicted in Scheme 2,details of which are given below

Step-1

Compound of formula (Ia) where R¹ is H, can be converted to compound offormula (I) by reacting compound of I with R¹Z (Z is any suitableleaving group like Cl, Br, I, —O(SO)₂(4-MePh), —O(SO)₂CH₃, —O(SO)₂CF₃etc.) in presence of a suitable base like 2,6-Lutidine,1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂CO₃, Cs₂CO₃, NaH, KH,n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solventlike THF, DMF, DMSO etc., at temperature ranging from about −78° C. toabout 150° C.

Scheme-3:

Compound of formula (I) where R¹ is selected from the group consistingof substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-alkynyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl, can be prepared as depicted in Scheme 3,details of which are given below

Step-1

Compound of formula (II) where R¹ is selected from the group consistingof substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-alkynyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl, can be converted to compound of formula(III) by reacting compound of II (Z is any suitable leaving group likeCl, Br, I, —O(SO)₂(4-MePh), —O(SO)₂CH₃, —O(SO)₂CF₃ etc.) with R²NH₂ inpresence of a suitable base like 2,6-Lutidine,1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K₂CO₃, Cs₂CO₃, NaH, KH,n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solventlike THF, DMF, DMSO and the like, at temperature ranging from about −78°C. to about 150° C.

Step-2

Compound of formula-(III) where R¹ is selected from the group consistingof substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-alkynyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl, can be converted to compound of formula-(I)by reacting compound of formula (III) with suitable base such as NaOMe,K₂CO₃ etc. in a solvent like Methanol, Ethanol, THF, DMF etc. attemperature ranging from about −78° C. to about 150° C.

The intermediates and the compounds of the present invention areobtained in pure form in a manner known per se, for example bydistilling off the solvent in vacuum and re-crystallizing the residueobtained from a suitable solvent, such as pentane, diethyl ether,isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone ortheir combinations or subjecting it to one of the purification methods,such as column chromatography (e.g. flash chromatography) on a suitablesupport material such as alumina or silica gel using eluent such asdichloromethane, ethyl acetate, hexane, methanol, acetone and theircombinations. Preparative LC-MS method is also used for the purificationof molecules described herein.

Salts of compound of formula I are obtained by dissolving the compoundin a suitable solvent, for example in a chlorinated hydrocarbon, such asmethyl chloride or chloroform or a low molecular weight aliphaticalcohol, for example, ethanol or isopropanol, which was then treatedwith the desired acid or base as described in Berge S. M. et al.“Pharmaceutical Salts, a review article in Journal of Pharmaceuticalsciences volume 66, page 1-19 (1977)” and in handbook of pharmaceuticalsalts properties, selection, and use by P. H. Einrich Stahland CamilleG. wermuth, Wiley-VCH (2002).

The stereoisomers of the compounds of formula I of the present inventionmay be prepared by stereospecific syntheses or resolution of the achiralcompound using an optically active amine, acid or complex forming agent,and separating the diastereomeric salt/complex by fractionalcrystallization or by column chromatography.

The following examples are provided to further illustrate the presentinvention and therefore should not be construed in any way to limit thescope of the present invention. All ¹HNMR spectra were determined in thesolvents indicated and chemical shifts are reported in δ units downfieldfrom the internal standard tetramethylsilane (TMS) and interprotoncoupling constants are reported in Hertz (Hz).

EXAMPLES

Unless otherwise stated, work-up includes distribution of the reactionmixture between the organic and aqueous phase indicated withinparentheses, separation of layers and drying the organic layer oversodium sulphate, filtration and evaporation of the solvent.Purification, unless otherwise mentioned, includes purification bysilica gel chromatographic techniques, generally using a mobile phasewith suitable polarity. The following abbreviations are used in thetext: DMSO-d6: Hexadeuterodimethyl sulfoxide; DMSO: Dimethylsulfoxide,CDI: 1,1′-Carbonyldiimidazole, DMF: N,N-dimethyl formamide, DMA:Dimethylacetamide, HBTU: 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, THF: Tetrahydrofuran, DCM:Dichloromethane, EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide,HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate, DIPEA: N,N-Diisopropyl ethyl amine, HOBT:1-Hydroxy-1H-benzotriazole, J: Coupling constant in units of Hz, RT orrt: room temperature (22-26° C.), Aq.: aqueous, AcOEt: ethyl acetate,equiv. or eq.: equivalents and hr. or h: hour(s);

The following examples demonstrate preparation of few representativecompounds embodied in formula (I); however, the same should not beconstrued as limiting the scope of the invention.

Intermediates Intermediate-i: Preparation of(3-aminophenyl)(azetidin-1-yl)methanone

Step a: Synthesis of 3-((tert-butoxycarbonyl)amino)benzoic acid

To a stirred solution of 3-aminobenzoic acid (5 g, 36.5 mmol) in water(40.0 ml) was added aq. solution of sodium hydroxide (2.187 g, 54.7mmol) followed by (BOC)₂O (10.16 ml, 43.8 mmol) in dioxane (20.0 ml)under ice cooling. The mixture was stirred under ice cooling for 30 minand further at room temperature for 12 hrs. To the reaction mixtureethyl acetate (50.0 ml) was added and the aq. layer was separated. Theaq. layer was acidified up to pH 4 using 2N HCl and precipitatedcrystals were collected by filtration (7.2 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 12.80 (brs, 1H), 9.54 (s, 1H), 8.14 (s, 1H),7.62 (dd, 1H, J=0.8 Hz, J=8 Hz), 7.54-7.52 (m, 1H), 7.35 (t, 1H, J=7.6Hz), 1.48 (s, 9H).

Step b: Synthesis of tert-butyl (3-(azetidine-1-carbonyl)phenyl)carbamate

To a stirred solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (1.5g, 6.32 mmol) in DMF (15 ml) were added N,N-diisopropyl ethylamine(2.208 ml, 12.64 mmol) and o-Benzotriazol-1-yl-tetramethyluroniumhexafluorophosphate (2.398 g, 6.32 mmol) followed by azetidinehydrochloride (1.183 g, 12.64 mmol) at room temperature, under nitrogenatmosphere. The reaction was stirred at room temperature for 24 h andmonitored by TLC. To the reaction mixture, water (25.0 ml) was added andextracted with ethyl acetate (30 ml×3). The aqueous layer wasre-extracted with ethyl acetate. All organic layers were combined andwashed with cold water (20.0 ml) and brine (20 ml); dried over sodiumsulphate and solvent was evaporated under vacuum to get the titledcompound (1.1 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 7.74-7.73 (m, 1H), 7.56-7.52(m, 1H), 7.31 (t, 1H, J=8 Hz), 7.19-7.16 (m, 1H), 4.25 (t, 2H, J=8 Hz),4.01 (t, 2H, J=7.6), 2.32-2.22 (m, 2H), 1.47 (s, 9H). ESI-MS: [m/z:277.09 (M+1)].

Step c: Synthesis of (3-aminophenyl)(azetidin-1-yl)methanone

To a stirred solution of tert-butyl (3-(azetidine-1-carbonyl)phenyl)carbamate (600 mg, 2.171 mmol) in DCM (5.0 ml) was added trifluoroaceticacid (0.167 ml, 2.171 mmol) at 0° C. under nitrogen atmosphere. Reactionwas stirred at room temperature for 1 hr. Solvent evaporated up todryness and the residual solid was dissolved in DCM (20 ml) and washedwith saturated solution of NaHCO₃. DCM layer was dried over sodiumsulphate and evaporated under vacuum. Resulting solid was washed withpentane and ether to give the titled compound (310 mg).

¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (t, 1H, J=8 Hz), 6.80 (t, 1H, J=2 Hz),6.70-6.67 (m, 1H), 6.65-6.62 (m, 1H), 5.24 (s, 2H), 4.25 (t, 2H, J=7.6Hz), 3.98 (t, 2H, J=7.6 Hz), 2.24-2.18 (m, 2H). GCMS: 176.13 [M+].

Intermediate-ii: Synthesis of 2-(3-aminophenyl)-N-cyclopropylacetamide

Step a: Synthesis of N-cyclopropyl-2-(3-nitrophenyl)acetamide

To a stirred solution of 2-(3-nitrophenyl)acetic acid (2.5 g, 13.80mmol) in DMF (20 ml) was added HBTU (4.19 g, 16.56 mmol),N,N-diisopropyl ethylamine (4.82 ml, 27.6 mmol) followed by addition ofcyclopropylamine (1.946 ml, 27.6 mmol) at room temperature undernitrogen atmosphere. Reaction mixture was stirred at room temperaturefor 16 hrs, the reaction mixture was diluted with water (80.0 mL) andextracted with ethyl acetate (20.0 ml×3). Combined organic layers werewashed with cold water (20.0 ml) and brine (10.0 ml); dried over sodiumsulphate. The solvent was evaporated under vacuum to give the crudecompound which was purified by column chromatography to afford titledcompound (2.41 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 8.25 (d, 1H, J=2.4 Hz), 8.12-8.09 (m, 1H),7.67 (d, 1H, J=7.6 Hz), 7.60 (t, 1H, J=7.6 Hz), 3.52 (s, 2H), 2.63-2.58(m, 1H), 0.63-0.55 (m, 2H), 0.41-0.37 (m, 2H). GCMS: 221.09 [M+]

Step b: Synthesis of 2-(3-aminophenyl)-N-cyclopropylacetamide

To a stirred solution of N-cyclopropyl-2-(3-nitrophenyl) acetamide (2.4g, 10.90 mmol) in methanol (25.0 ml) was added slurry of Pd/C (10%,0.232 g), To the above reaction mixture, triethylsilane (8.70 ml, 54.5mmol) was added slowly drop wise at room temperature (reaction wasexothermic) and then the reaction mixture was stirred at roomtemperature for 1 hr. The reaction mixture was filtered through celitebed and the filtrate was evaporated under vacuum. The residue wastriturated in hexane, the solid obtained was filtered and dried undervacuum to give the product (1.95 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (s, 1H), 6.90 (t, 1H, J=7.6 Hz),6.49-6.35 (m, 1H), 5.02 (s, 2H), 3.15 (s, 2H), 2.60-2.59 (m, 1H),0.69-0.58 (m, 2H), 0.48-0.38 (m, 2H). GCMS: 190.11 [M+].

Intermediate-iii: Synthesis of 2-(3-aminophenoxy)-N-cyclopropylacetamide

Step a: Synthesis of N-cyclopropyl-2-(3-nitrophenoxy)acetamide

A mixture of 3-nitrophenol (4 g, 28.8 mmol),2-chloro-N-cyclopropylacetamide (4.61 g, 34.5 mmol), K₂CO₃ (7.95 g, 57.5mmol) and 18-CROWN-6 (0.228 g, 0.863 mmol) in N,N-Dimethylformamide(30.0 ml) was stirred under N₂ atmosphere for 18 hrs at 50° C. Aftercooling to RT, the reaction mixture was partitioned between EtOAc (250ml) and water (250 ml). Aq. phase was re-extracted with EtOAc (200 ml).Combined organic layer was washed with brine (100 ml), dried over sodiumsulphate and the solvent was evaporated under vacuum. Crude residue waspurified by flash chromatography to obtainN-cyclopropyl-2-(3-nitrophenoxy)acetamide (4.21 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 7.85-7.82 (m, 1H), 7.76-7.74 (m, 1H), 7.59(t, J=8.4 Hz, 1H), 7.44-7.41 (m, 1H), 4.60 (s, 2H), 2.72-2.66 (m, 1H),0.67-0.60 (m, 2H), 0.50-0.46 (m, 2H). GCMS: 236.14 [M+].

Step b: Synthesis of 2-(3-aminophenoxy)-N-cyclopropylacetamide

Triethylsilane (27.0 ml, 169 mmol) was added dropwise to a suspension ofN-cyclopropyl-2-(3-nitrophenoxy)acetamide (4 g, 16.93 mmol) and Pd/C(10%, 400 mg) in MeOH (50 ml). Resulting suspension was stirred at RTfor 20 min. and filtered through celite. The filtrate was evaporatedunder vacuum and triturated in hexane to obtain the crystals which werecollected by filtration to afford2-(3-aminophenoxy)-N-cyclopropylacetamide (2.86 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 6.89 (t, J=8.0 Hz, 1H), 6.18-6.12 (m, 2H),6.07-6.04 (m, 1H), 5.21 (brs, 1H), 5.08 (s, 2H), 4.29 (s, 2H), 2.70-2.66(m, 1H), 0.62-0.59 (m, 2H), 0.50-0.45 (m, 1H). GCMS: 206.11 [M+].

Intermediate-iv: Synthesis of(3-aminophenyl)(1,1-dioxidothiazolidin-3-yl)methanone

Step a: Synthesis of (3-nitrophenyl)(thiazolidin-3-yl)methanone

To a stirred solution of 3-nitrobenzoyl chloride (5.00 g, 26.9 mmol) inDCM (50 ml), thiazolidine (3.60 g, 40.4 mmol) was added at 0° C.Triethylamine, (7.51 ml, 53.9 mmol) was added dropwise into the reactionmixture over 5 min and the reaction mixture was stirred at RT for 1 hr.Reaction mixture was diluted with cold water. Organic phase wasseparated and aq. phase was extracted using DCM (3×10.0 ml). Combinedorganic layer was washed with brine (100 ml), dried over sodium sulphateand the solvent was evaporated under vacuum to afford the title compound(5.0 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.35-8.31 (m, 2H), 8.01-7.98 (m, 1H), 7.79(t, 1H, J=8 Hz), 4.65-4.52 (m, 2H), 3.84-3.70 (m, 2H), 3.08-2.97 (m,2H). GCMS: 237.96 [M+].

Step b: Synthesis of (1,1-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone

To a stirred solution of (3-nitrophenyl)(thiazolidin-3-yl)methanone (4g, 16.79 mmol) in acetic acid (30 ml), H₂O₂(12 ml, 30% solution) wasadded, the resulting mixture was stirred at 100° C. for 3 hrs. Themixture was concentrated under vacuum and the residue was treated MeOH.Resulting solid was filtered off and dried under vacuum to afford thetitled compound (3 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.39-8.32 (m, 2H), 7.99-7.97 (m, 1H), 7.79(t, 1H J=7.6 Hz), 4.69 (s, 2H), 4.20-3.90 (m, 2H), 3.51-3.47 (m, 2H).ESI-MS: [m/z: 270.08 (M+1)].

Step c: Synthesis of(3-aminophenyl)(1,1-dioxidothiazolidin-3-yl)methanone

A solution of (1,1-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone (3g, 11.10 mmol) in MeOH (30 ml) and 10% Pd—C (300 mg) was stirred underH₂ (1 atm) for overnight. Reaction mixture was filtered through celitepad and the filtrate was evaporated under vacuum to afford the titledcompound (2.3 gm).

¹HNMR (400 MHz, DMSO-d6), δ 7.12-7.08 (m, 1H), 6.84-6.70 (m, 1H),6.61-6.59 (d, 1H, J=8 Hz), 5.35 (s, 2H), 4.60 (s, 2H), 4.05-4.00 (m,2H), 3.45-3.41 (m, 2H). ESI-MS: [m/z=241.71 (M+1)].

Intermediate-v: Synthesis of (3-aminophenyl)(1,1-dioxidothiomorpholino)methanone

Step a: Synthesis of (3-nitrophenyl)(thiomorpholino)methanone

To a suspension of 3-nitrobenzoic acid (6.5 g, 38.9 mmol) in DCM (50 ml)was added oxalyl chloride (5 ml, 58.1 mmol) and DMF (0.5 ml, 6.46 mmol),respectively. The resulting mixture was stirred at room temperatureuntil a clear solution was formed. The solvent was removed under vacuum.3-Nitrobenzoyl chloride thus obtained was dissolved in DCM (50 ml), Et₃N(10.13 ml, 72.7 mmol) and thiomorpholine (5 g, 48.5 mmol) were added at0° C. Reaction mixture was gradually allowed to reach to roomtemperature and stirred for 2 hrs. The reaction mixture was concentratedunder vacuum and cold water was added to the residue, the solid obtainedwas filtered and dried under vacuum to give the product (9.2 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.30-8.28 (m, 1H), 8.26-8.22 (m, 1H),7.87-7.84 (m, 1H), 7.74 (t, 1H, J=8 Hz), 3.88 (brs, 2H), 3.52 (brs, 2H),2.71 (brs, 2H), 2.60 (brs, 2H). ESI-MS: [m/z=252.7 (M+1)].

Step b: Synthesis of (1,1-dioxidothiomorpholino) (3-nitrophenyl)methanone

To a stirred solution of (3-nitrophenyl)(thiomorpholino)methanone (12 g,47.6 mmol) in acetic acid (80 ml) was added H₂O₂(45 ml, 30% solution),reaction mixture was heated at 90° C. for 3 hr. Solvents were evaporatedunder vacuum, the residue was dissolved in DCM:MeOH (20:20 mL) andpassed through a celite bed. The filtrate was concentrated under vacuumto obtain the crude product (7.3 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.41-8.40 (m, 1H), 8.33-8.30 (m, 1H),7.94-7.91 (m, 1H), 7.76 (t, 1H, J=8 Hz), 4.03 (brs, 2H), 3.66 (brs, 2H),3.33-3.16 (m, 4H). ESI-MS: [m/z=284.6 (M+1)].

Step c: Synthesis of (3-aminophenyl)(1,1-dioxidothiomorpholino)methanone

To a stirred solution of(1,1-dioxidothiomorpholino)(3-nitrophenyl)methanone (3.5 g, 12.31 mmol)in MeOH (20 ml) was added Pd—C (10%, 350 mg) followed by slow additionof triethylsilane (8.5 ml) at RT. Reaction was stirred at RT for 1 h.Reaction mixture was filtered through celite and washed with methanol(50 ml). Filtrate was concentrated under vacuum and triturated in hexaneto get crude product (2.8 gm).

¹HNMR (400 MHz, DMSO-d6), δ 7.08-7.05 (t, 1H, J=7.6 Hz), 6.63-6.56 (m,3H), 5.28 (s, 2H), 3.94-3.73 (m, 4H), 3.16 (brs, 4H). GCMS: 254.09 [M+]

Intermediate-vi: Synthesis of 2-(3-aminophenyl)-2-methylpropanamide

Step a: Synthesis of 2-methyl-2-(3-nitrophenyl)propanenitrile

To an ice-cold slurry of 50% NaH (6.84 g, 171 mmol) in anhydrous THF(30.0 ml) was slowly added a solution of 2-(3-nitrophenyl) acetonitrile(4.2 g, 25.9 mmol) in anhydrous THF (30 ml). After 30 min, methyl iodide(12.63 ml, 202 mmol) was slowly added. The reaction mixture was allowedto warm to room temperature and stirred overnight. It was then quenchedwith ice-water. The reaction mixture was then extracted with ethylacetate, the organic layer was separated and washed with water, driedover anhydrous sodium sulphate; filtered and concentrated to get crudeoil. The crude oil was purified by column chromatography over silica gelby eluting with ethyl acetate/hexane (5:95) gave2-methyl-2-(3-nitrophenyl) propanenitrile (2.1 g).

¹HNMR (400 MHz, CDCl3), δ 8.33-8.32 (m, 1H), 8.24-8.21 (m, 1H),7.92-7.89 (m, 1H), 7.63 (t, J=8.00 Hz, 1H), 1.82 (s, 6H). GCMS:190.11[M+]

Step b: Synthesis of 2-methyl-2-(3-nitrophenyl)propanamide

To a solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (1.5 g, 7.89mmol) in 2-propanol was added benzyltriethyl ammonium chloride (0.054 g,0.237 mmol) and 25% aq. KOH solution (5.0 ml). Resulting solution wasstirred for 5 min. and H₂O₂(2.5 ml, 30% aq. solution) was added (slowaddition). Reaction mixture was heated at 75° C. for 4 hr. Solvent wasevaporated under vacuum and residue was suspended in water (200 ml).Precipitate was filtered and dried to obtain 2-methyl-2-(3-nitrophenyl)propanamide (0.98 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.15-8.10 (m, 2H), 7.80 (d, J=7.6 Hz, 1H),7.64 (t, J=8.00 Hz, 1H), 7.11 (brs., 1H), 7.05 (brs., 1H) 1.50 (s, 6H).

Step c: Synthesis of 2-(3-aminophenyl)-2-methylpropanamide

To a stirred solution of 2-methyl-2-(3-nitrophenyl) propanamide (0.9 g,4.32 mmol) in methanol was added Pd—C (10%, 0.23 g) followed by slowaddition of triethylsilane (6.90 ml, 43.2 mmol) at RT. Reaction wasstirred at same temperature for 25 min. The reaction mixture wasfiltered through celite bed and washed with methanol (50 ml). Filtratewas collected and concentrated under vacuum to obtain2-(3-aminophenyl)-2-methylpropanamide (0.611 g).

¹HNMR (400 MHz, DMSO-d6), δ 6.93 (t, J=8.0 Hz, 1H), 6.78 (brs., 1H),6.72 (brs., 1H), 6.55-6.47 (m, 2H), 6.41-6.38 (m, 1H), 4.98 (s, 2H),1.35 (s, 6H). GCMS: 178.15 [M+].

Intermediate-vii: Synthesis of 2-(3-aminophenyl)-2,2-difluoroacetamide

Step a: Synthesis of Ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate

To a solution of 1-iodo-3-nitrobenzene (1.450 g, 5.82 mmol) and ethyl2-bromo-2,2-difluoroacetate (1.3 g, 6.40 mmol) in anhydrous DMSO (10 ml)was added Copper powder (0.740 g, 11.64 mmol). The mixture was purgedwith N₂ and heated at 70° C. in a sealed vial for 17 h. After beingcooled to room temperature, the reaction mixture was poured into 20%aqueous NH₄Cl solution (100 mL) and was extracted with EtOAc (2×100 mL).The organic extract was washed with brine (2×30 mL), dried over Na₂SO₄and concentrated. The residue was purified by flash chromatography toobtain ethyl 2, 2-difluoro-2-(3-nitrophenyl) acetate (0.714 g).

¹HNMR (400 MHz, DMSO-d6), δ 8.47 (d, J=6.8 Hz, 1H), 8.33 (s, 1H), 8.09(dd, J=0.8 & 8 Hz, 1H), 7.89 (t, J=8.4 Hz, 1H), 4.3 (q, J=9.2 Hz, 2H),1.24 (t, J=6.4 Hz, 3H). GCMS: 245.15 [M+].

Step b: Synthesis of 2,2-difluoro-2-(3-nitrophenyl) acetamide

A solution of ethyl 2, 2-difluoro-2-(3-nitrophenyl) acetate (0.701 g,2.86 mmol) in Methanolic ammonia (7M, 20.0 ml) was taken in sealed tube.Resulting mixture was heated at 75° C. for 3 hrs. The reaction mixturewas concentrated under vacuum and cold water was added to obtain theprecipitate. Solid was filtered to obtain 2,2-difluoro-2-(3-nitrophenyl) acetamide (0.515 g).

¹HNMR (400 MHz, DMSO-d6), δ 8.55 (brs., 1H), 8.44-8.37 (m, 2H), 8.18(brs., 1H), 8.04 (d, J=7.6 Hz, 1H), 7.86 (t, J=8 Hz, 1H). GCMS: 215.98[M+]

Step c: Synthesis of 2-(3-aminophenyl)-2,2-difluoroacetamide

To a stirred solution of 2,2-difluoro-2-(3-nitrophenyl)acetamide (0.5 g,2.313 mmol) in methanol (20 ml) was added Pd—C (100 mg) followed by slowaddition of triethylsilane (3.7 ml, 23.13 mmol) at RT. The reaction wasstirred at same temperature for 30 min. The reaction mixture wasfiltered through celite bed and washed with methanol (50 ml). Filtratewas collected and concentrated under vacuum to get 2-(3-aminophenyl)-2,2-difluoroacetamide (0.301 g).

¹HNMR (400 MHz, DMSO-d6), δ 8.21 (brs., 1H), 7.90 (brs., 1H), 7.11 (t,J=7.6 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=7.6 Hz, 2H), 5.42 (s, 2H). GCMS:186.01 [M+].

Intermediate-viii: Synthesis of 2-(3-aminophenyl)-N,N-dimethylacetamide

Step a: Synthesis of N,N-dimethyl-2-(3-nitrophenyl)acetamide

To a stirred solution of 2-(3-nitrophenyl) acetic acid (0.2 g, 1.104mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). resultingmixture was heated at 50° C. for 1 hr, cooled to room temperature andthen dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et₃N (0.15ml, 1.104 mmol) were added sequentially. Resulting reaction mixture wasstirred for 24 h at ambient temperature. Solvents were evaporated undervacuum. The residue was purified by flash chromatography to obtainN,N-dimethyl-2-(3-nitrophenyl) acetamide (0.192, 84% yield).

¹HNMR (400 MHz, DMSO-d6), δ 8.11-8.08 (m, 2H), 7.68-7.58 (m, 2H), 3.89(s, 2H), 3.05 (s, 3H), 2.85 (s, 3H). GCMS: 208.12 [M+].

Step b: Synthesis of 2-(3-aminophenyl)-N,N-dimethylacetamide

To a stirred solution of N,N-dimethyl-2-(3-nitrophenyl)acetamide (1.6 g,7.68 mmol) in methanol (20 ml) was added 10% Pd—C (0.327 g) followed byslow addition of triethylsilane (12.3 ml, 77 mmol) at RT. Reaction wasstirred at same temperature for 30 min. The reaction mixture wasfiltered through celite bed. The filtrate was concentrated to get2-(3-aminophenyl)-N, N-dimethylacetamide (1.21 g, 88% yield).

¹HNMR (400 MHz, DMSO-d6), δ 6.92 (t, J=7.6 Hz, 1H), 6.43-6.34 (m, 3H),5.05 (s, 2H), 3.49 (s, 2H), 2.95 (s, 3H), 2.81 (s, 3H). GCMS: 178.15[M+].

Intermediate-ix: Synthesis of 3-(3-aminophenyl)-N-methylpropanamide

Step a: Synthesis of N-methyl-3-(3-nitrophenyl)acrylamide

To a solution of 3-nitrocinnamic acid (5.0 g) in dry Toluene (100 ml),oxalyl chloride (11.33 ml) was carefully added, followed by dry DMF (0.1mL). The resulting yellow solution was refluxed for 3 hrs and thenevaporated to dryness, to get the 3-nitro cinnamoyl chloride as a solidresidue, This solid residue was dissolved in THF, the resulting solutionwas cooled at 0° C., and 2M methylamine (13 ml) was added to thereaction mixture, the reaction mixture was stirred for 30 min. Solventswere evaporated under vacuum, the crude material was re-crystallisedfrom diethylether to afford the title compound (4 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.38 (s, 1H), 8.26-8.25 (d, 1H J=4.4 Hz),8.20-8.18 (m, 1H), 8.02-8.00 (d, 1H J=7.6 Hz), 7.72-7.68 (m, 1H)7.56-7.52 (d, 1H J=16 Hz), 6.85-6.81 (d, 1H, J=15.6 Hz), 2.71-2.70 (d,3H J=4.4 Hz). GCMS: 207.05 [M+].

Step b: Synthesis of 3-(3-aminophenyl)-methyl propanamide

To a stirred solution of N-methyl-3-(3-nitrophenyl)acrylamide (4 g,19.40 mmol) and Pd—C (10%, 200 mg) in MeOH (30.0 ml) was addedtriethylsilane (31 ml, 194 mmol) dropwise at room temperature over aperiod of 1 hr. Reaction progress was monitored by TLC. After completionof reaction, reaction mixture was filtered through celite bed. Thefiltrate was concentrated under vacuum to give the title compound (2.5gm).

¹HNMR (400 MHz, DMSO-d6), δ 7.76-7.75 (d, 1H, J=4 Hz), 6.96-6.88 (m,1H), 6.38-6.32 (m, 3H), 5.10 (s, 2H), 2.62-2.58 (t, 2H J=6.8 Hz),2.55-2.54 (d, 3H J=4.4 Hz) 2.32-2.25 (t, 2H J=6.9 Hz). GCMS: 177.88[M+].

Intermediate-x: Synthesis of(3-aminophenyl)(4-hydroxypiperidin-1-yl)methanone

Step a: Synthesis of (4-hydroxypiperidin-1-yl)(3-nitrophenyl) methanone

To a stirred solution of 3-nitrobenzoyl chloride (10.0 g, 53.9 mmol) inDCM (10 ml) was added piperidin-4-one hydrochloride (10.96 g, 81.0 mmol)and triethylamine (22.53 ml, 162.0 mmol). The reaction mixture wasstirred at room temperature for 30 min and evaporated to dryness. Thecrude material was treated with diethyl ether, solid obtained wasfiltered and dried under vacuum to give the title compound (9.0 gm).

¹HNMR (400 MHz, CDCl₃), δ 8.35-8.32 (m, 2H), 7.82 (d, 1H, J=7.6 Hz),7.69-7.65 (m, 1H), 4.12 (bs, 2H), 3.77 (bs, 2H), 2.55 (bs, 4H). GCMS:248.11 [M+].

Step-b: Synthesis of (4-hydroxypiperidin-1-yl)(3-nitrophenyl)methanone

To a stirred solution of 1-(3-nitrobenzoyl) piperidin-4-one (1.5 g, 6.04mmol) in THF: Methanol (20 mL, 1:1), was added sodium borohydride (0.229g, 6.04 mmol) at room temp. Reaction mixture was stirred at roomtemperature for 30 min. and diluted with water (20.0 ml), extracted withethyl acetate (3×30.0 ml). Combined organic layer was dried over sodiumsulphate and the solvents were removed under vacuum to obtain the titlecompound. (1 gm).

¹HNMR (400 MHz, DMSO-d6), δ 8.30-8.27 (m, 1H), 8.17-8.16 (m, 1H),7.85-7.83 (m, 1H), 7.74 (t, 1H, J=7.6 Hz), 4.81 (bs, 1H), 3.98 (bs, 1H),3.77-3.72 (m, 1H), 3.42 (bs, 1H), 3.28 (bs, 1H), 3.13 (bs, 1H), 1.68(bs, 1H), 1.53 (bs, 1H) 1.42 (bs, 1H) 1.35 (bs, 1H). GCMS: 250.19 [M+].

Step-c: Synthesis of (3-aminophenyl)(4-hydroxypiperidin-1-yl) methanone

T o a stirred solution of(4-hydroxypiperidin-1-yl)(3-nitrophenyl)methanone (1 g, 4.00 mmol) andPd—C (10%, 0.425 g) in Methanol (10 ml) was added triethylsilane (3.19ml, 19.98 mmol) dropwise at room temperature. The reaction mixture wasfiltered through celite bed. The filtrate was concentrated under vacuumto give the title compound. (0.8 gm)

¹HNMR (400 MHz, DMSO-d6), δ 7.03 (t, 1H, J=8 Hz), 6.58 (dd, 1H, J=8.0and 1.6 Hz), 6.51-6.50 (m, 1H), 6.42 (d, 1H, J=7.2 Hz), 5.23 (s, 1H),4.78 (d, 1H, J=3.6 Hz), 3.98 (bs, 1H), 3.73-3.69 (m, 1H), 3.50 (bs, 1H),3.13 (bs, 2H), 1.70 (bs, 2H), 1.30 (bs, 2H). GCMS: 220.15 [M+].

Intermediate-xi: Synthesis of 3-Amino-N-(oxetan-3-yl)benzamide

Step-a: Synthesis of 3-Nitro-N-(oxetan-3-yl)benzamide

3-Nitrobenzoic acid (0.50 g, 2.99 mmol), oxetan-3-amine (0.219 g, 2.99mmol) were taken in pyridine (0.5 ml) and under nitrogen atmosphere andEDC.HCl (0.574 g, 2.99 mmol) was added. The reaction mixture was stirredat room temperature for 10 hrs. After completion of reaction, thereaction mixture was diluted with water (5 ml) and extracted with ethylacetate (2×5 ml). Combined organic layer was dried over sodium sulfateand concentrated under vacuum to afford the title compound (600 mg).

¹HNMR (400 MHz, CDCl₃): δ 8.64 (t, 1H, J=2 Hz), 8.43-8.40 (m, 1H),8.21-8.18 (m, 1H), 7.85 (bs, 1H), 7.70 (t, 1H, J=8 Hz), 5.33-5.23 (m,1H), 5.07 (t, 2H, J=7.2 Hz), 4.66 (t, 2H, J=6.8 Hz).

Step-b: Synthesis of 3-Amino-N-(oxetan-3-yl)benzamide

To a stirred solution of 3-Nitro-N-(oxetan-3-yl) benzamide (0.06 g,0.270 mmol) in methanol (5 ml) was added Pd/C (2.87 mg) and the reactionmixture was stirred under hydrogen atmosphere for 20 min. The reactionmixture was diluted with methanol (10 ml) and the mixture was filteredthrough celite, and the filtrate was concentrated under vacuum to affordthe title compound (48 mg).

¹HNMR (400 MHz, CDCl₃): δ 7.25-7.21 (m, 1H), 7.15-7.14 (m, 1H),7.09-7.07 (m, 1H), 6.85-6.82 (m, 1H), 6.55 (bs, 1H), 5.29-5.08 (m, 1H),5.06-4.98 (m, 2H), 4.64-4.60 (m, 2H), 3.95-3.85 (bs, 2H). GCMS: 192(M+).

Intermediate-xii: Synthesis of 3-Amino-N-(tetrahydrofuran-3-yl)benzamide

Step-a: Synthesis of 3-Nitro-N-(tetrahydrofuran-3-yl) benzamide

Tetrahydrofuran-3-amine (0.1 g, 1.148 mmol) and 3-nitrobenzoic acid(0.192 g, 1.148 mmol) were taken in pyridine (2 ml), to the mixtureEDC.HCl (0.220 g, 1.148 mmol) was added, the reaction mixture wasstirred under nitrogen for 10 hrs at room temperature. The reactionmixture was diluted with cold water (15 ml), extracted with ethylacetate (2×10 ml). Combined organic layer was washed with satd. aq. sodbicarbonate and dil HCl, the organic layer was dried over sodium sulfateand concentrated under vacuum to afford the title product (240 mg).

¹HNMR (400 MHz, CDCl₃): □ 8.62-8.61 (m, 1H), 8.39-8.36 (m, 1H),8.19-8.17 (m, 1H), 7.67 (t, 1H, J=8 Hz), 6.62 (d, 1H, J=6 Hz), 4.79-4.75(m, 1H), 4.08-4.00 (m, 1H), 3.93-3.83 (m, 3H), 2.44-2.37 (m, 1H),2.01-1.98 (m, 1H).

Step-b: Synthesis of 3-Amino-N-(tetrahydrofuran-3-yl) benzamide

3-Nitro-N-(tetrahydrofuran-3-yl) benzamide (0.24 g, 1.016 mmol) wastaken in methanol (5 ml), added Pd—C (10%, 0.108 g) and the reactionmixture was stirred under hydrogen atmosphere for 2 hr at roomtemperature. After completion of the reaction, the reaction mixture wasfiltered and the filtrate was concentrated under vacuum to afford thecrude product, which was purified by column chromatography eluting with0-100% ethyl acetate in hexane to obtain the title compound (180 mg).

¹HNMR (400 MHz, CDCl₃): □ 7.21 (t, 1H, J=7.6 Hz), 7.13-7.12 (m, 1H),7.05-7.03 (m, 1H), 6.82-6.80 (m, 1H), 6.24 (bs, 1H), 4.74-4.71 (m, 1H),4.04-3.77 (m, 6H), 2.39-2.32 (m, 1H), 1.94-1.91 (m, 1H). GCMS: 206 (M+).

Intermediate-xiii: Synthesis of 2-(3-aminophenyl-2-hydroxyacetamide

Step-a: Synthesis of (Tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide

Under nitrogen atmosphere, zinc chloride (8.12 g, 59.6 mmol) andmolecular sieve (200 mg) were taken in THF (10 ml) at room temperature.To the above mixture 3-nitrobenzaldehyde (3.00 g, 19.85 mmol),N-methylhydroxylamine hydrochloride (2.65 g, 31.8 mmol) and sodiumbicarbonate (2.67 g, 31.8 mmol) were added. The mixture was stirred atroom temperature for 30 min., followed by addition of2-isocyano-2-methylpropane (3.30 g, 39.7 mmol) and acetic acid (3.58 g,59.6 mmol) and the reaction mixture was stirred for 48 hrs. Water (50ml) was added and the mixture was extracted with ethyl acetate (2×50ml). Combined organic layer was washed with aq. satd. sodium bicarbonatesolution and water and dried over sodium sulfate. The mixture wasconcentrated under vacuum and the crude product obtained was purified bycolumn chromatography to afford the yellow oil (2.4 gm).

¹HNMR (400 MHz, CDCl₃): □ 9.18 (t, 1H, J=2 Hz), 8.73-8.70 (m, 1H),8.49-8.45 (m, 1H), 7.69 (t, 1H, J=8.0 Hz), 7.03 (bs, 1H), 1.48 (s, 9H).

Step-b: Synthesis of 2-(3-nitrophenyl)-2-oxoacetamide

Under nitrogen atmosphere, (tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide(1.50 g, 5.99 mmol) was taken in toluene (10 ml) at room temperature,tert-butyldimethylsilyl trifluoromethane sulfonate (1.378 ml, 5.99 mmol)was added and the reaction mixture was heated at 100° C. for 8 hrs. Thereaction mixture was concentrated under vacuum and satd. sodiumbicarbonate solution was added, the mixture was extracted with ethylacetate (3×20 ml). Combined organic layer was dried over sodium sulfateand the mixture was concentrated under vacuum to afford the crudeproduct, which was purified by column chromatography to afford yellowsolid product (440 mg).

¹HNMR (400 MHz, CDCl₃): □ 9.20 (t, 1H, J=2 Hz), 8.74-8.72 (m, 1H),8.52-8.49 (m, 1H), 7.73 (bs, 1H), 7.03 (bs, 1H), 5.78 (bs, 1H).

Step-c: Synthesis of 2-(3-aminophenyl-2-hydroxyacetamide

To a mixture of 2-(3-nitrophenyl)-2-oxoacetamide (1.00 g, 5.15 mmol),ammonium formate (0.974 g, 15.45 mmol) and methanol (20 ml) at 0° C.,was added Pd/C (10%, 0.17 g) and the reaction mixture was stirred atroom temperature for 18 hrs. The reaction mixture filtered throughcelite, the filtrate was concentrated under vacuum. The residue wastaken in ethyl acetate and filtered through celite and concentratedunder vacuum to afford the yellow solid product (330 mg).

¹HNMR (400 MHz, DMSO-d6): □ 7.24 (s, 1H), 7.12 (s, 1H), 6.93 (t, 1H,J=7.6 Hz), 6.6 (s, 1H), 6.55 (d, 1H, J=7.6 Hz), 6.44 (dd, 1H, J=1.2 and5.2 Hz), 5.78 (d, 1H, J=4 Hz), 5.01 (bs, 1H), 4.64 (d, 1H, J=3.2 Hz).GCMS: 166 [M+].

Intermediate-xiv Synthesis of3-Amino-N-(tetrahydro-2H-pyran-4-yl)benzamide

Step-a: Synthesis of 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide

Under nitrogen atmosphere, 3-nitrobenzoic acid (1.00 g, 5.98 mmol) wastaken in THF (20 ml) and the mixture was cooled to 0° C. followed byaddition of N-methylmorpholine (0.855 ml, 7.78 mmol) and ethylchloroformate (6.58 mmol). The reaction mixture was stirred for 30 minat 0° C. and tetrahydro-2H-pyran-4-amine (0.6 ml, 5.98 mmol) was addedand the reaction mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated under vacuum and the residue was takenin ethyl acetate (20 ml), washed with water and brine, dried over sodiumsulfate and concentrated under vacuum to afford the solid product (1.2gm).

Step-b: Synthesis of 3-Amino-N-(tetrahydro-2H-pyran-4-yl)benzamide

To a mixture of 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide (360 mg,1.439 mmol), ammonium formate (272 mg, 4.32 mmol) in methanol (20 ml) at0° C., was added Pd/C (10%, 0.04 g) and the reaction mixture was stirredat 60° C. for 1 hrs. The reaction mixture was cooled to room temperatureand filtered through celite, the filtrate was concentrated under vacuum.The residue was taken in ethyl acetate and the organic layer was washedwith water and brine, dried over sodium sulfate and concentrated undervacuum to afford the title compound (300 mg).

¹HNMR (400 MHz, DMSO-d₆): □ 7.21 (t, 1H, J=8 Hz), 7.14-7.13 (m, 1H),7.05 (d, 1H, J=7.6 Hz), 6.82-6.80 (m, 1H), 5.94 (d, 1H, J=6 Hz),4.22-4.18 (m, 1H), 4.03-4.00 (m, 2H), 3.98-3.80 (bs, 2H), 3.55 (t, 2H,J=9.6 Hz), 2.03-2.00 (m, 2H), 1.55-1.44 (m, 2H).

Intermediate-xv: Synthesis of2-(3-Aminophenyl)-1-(azetidin-1-yl)ethanone

Step-a: Synthesis of 1-(Azetidin-1-yl)-2-(3-nitrophenyl)ethanone

THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (1 g,5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2hrs at 0° C. followed by addition of triethylamine (2.308 ml, 16.56mmol) and azetidine hydrochloride (1.0-3 g, 11.04 mmol). The reactionmixture was stirred for 12 hrs at room temperature and then concentratedunder vacuum. The crude residue was purified by column chromatographyusing 0-50% ethyl acetate in hexanes as eluent to afford the titleproduct (0.53 g).

Step-b: Synthesis of 2-(3-Aminophenyl)-1-(azetidin-1-yl)ethanone

1-(Azetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.27 mmol) was takenin methanol (20 ml) and at 0° C., Pd—C (10%, 0.05 g) was added. Thereaction mixture was stirred under hydrogen atmosphere at roomtemperature for 5 hrs. The reaction mixture was filtered through celiteand the filtrate was concentrated under vacuum to afford the titleproduct (0.34 gm).

Intermediate-xvi: Synthesis of2-(3-Aminophenyl)-N-(oxetan-3-yl)acetamide

Step-a: Synthesis of 2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide

THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.8g, 4.42 mmol), CDI (1.07 g, 8.28 mmol), the mixture was stirred for 2hrs at 0° C. followed by addition of triethylamine (1.8 ml, 13.25 mmol)and oxetan-3-amine (0.484 g, 6.62 mmol). The reaction mixture wasstirred for 12 hrs at room temperature and then concentrated undervacuum. The crude residue was purified by column chromatography using0-50% ethyl acetate in hexanes as eluent to afford the title product(0.5 g).

Step-b: Synthesis of 2-(3-Aminophenyl)-N-(oxetan-3-yl)acetamide

2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide (0.5 g, 2.11 mmol) was takenin methanol (20 ml) and at 0° C., 10% Pd—C (0.5 g) was added. Thereaction mixture was stirred under hydrogen atmosphere at roomtemperature for 5 hrs. The reaction mixture was filtered through celiteand the filtrate was concentrated under vacuum to afford the titleproduct (0.42 gm).

Intermediate-xvii: Synthesis of2-(3-aminophenyl)-1-(3-hydroxyazetidin-1-yl)ethanone

Step-a: Synthesis of1-(3-Hydroxyazetidin-1-yl)-2-(3-nitrophenyl)ethanone

THF (30 mL) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.5g, 2.76 mmol), CDI (0.671 g, 4.14 mmol), the mixture was stirred for 2hrs at 0° C. followed by addition of triethylamine (1.2154 ml, 8.28mmol) and azetidin-3-ol hydrochloride (0.756 g, 6.90 mmol). The reactionmixture was stirred for 12 hrs at room temperature and then concentratedunder vacuum. The crude residue was purified by column chromatographyusing 0-50% ethyl acetate in hexanes as eluent to afford the titleproduct (0.51 g).

Step-b: Synthesis of2-(3-aminophenyl)-1-(3-hydroxyazetidin-1-yl)ethanone

1-(3-hydroxyazetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.117 mmol)was taken in methanol (20 ml) and at 0° C., Pd—C (10%, 0.5 g) was added.The reaction mixture was stirred under hydrogen atmosphere at roomtemperature for 5 hrs. The reaction mixture was filtered through celiteand the filtrate was concentrated under vacuum to afford the titleproduct (0.42 gm).

Intermediate xviii: Synthesis of3-(3-aminophenyl)-N-cyclopropylpropanamide

To a stirred solution of 3-(3-aminophenyl)propanoic acid (1 g, 6.05mmol) in 10 ml DMF, N-ethyl-N-isopropylpropan-2-amine (1.174 g, 9.08mmol), cyclopropanamine (0.415 g, 7.26 mmol) were added, resulting clearsolution was stirred at room temperature, HATU (3.45 g, 9.08 mmol) wasadded and the resulting mixture was stirred for 24 h at roomtemperature. Reaction Mixture was diluted with cold water and extractionwith Ethyl Acetate (3×30 ml). The Combined organic layer was dried oversodium sulphate and evaporated under reduced pressure to give the crudecompound, the crude compound was purified by column chromatography toafford the pure title compound (500 mg).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 7.89-7.85 (m, 1H), 6.92-6.83 (m, 1H),6.38-6.30 (m, 3H), 4.94 (brs, 2H), 2.68-2.63 (m, 1H), 2.57-2.51 (m, 2H),2.25-2.21 (m, 2H), 0.59-0.55 (m, 2H), 0.35-0.32 (m, 2H)

ESI-MS (m/z): 205.0 [M+1]

Intermediate xix: Synthesis of3-Amino-N-(1-carbamoylcyclopropyl)benzamide

Step-a: Synthesis of Ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate

To the suspension of 3-nitrobenzoic acid (1 g, 5.98 mmol) in pyridine(10 ml) ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.090 g,6.58 mmol) was added followed by EDC.HCl (1.721 g, 8.98 mmol) undernitrogen. Reaction mixture was stirred at room temperature for 3 hrs.Reaction mixture was diluted with cold water (100 ml) and extracted withethyl acetate (2×25 ml). Separated organic layer was washed with brineand water, dried over sodium sulfate and concentrated under vacuum tilldryness to obtain product (1.26 g, 76%).

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.59 (bs, 1H), 8.41-8.38 (m, 1H),8.20-8.18 (m, 1H), 7.68 (t, 1H, J=8 Hz), 6.82 (bs, 1H), 4.19 (q, 2H,J=7.2 Hz), 1.70-1.34 (m, 2H), 1.37-1.33 (m, 2H), 1.26 (t, 3H, J=7.2 Hz).

ESI-MS (m/z): 279.58 (M+1)

Step-b: Synthesis of 1-(3-Nitrobenzamido)cyclopropanecarboxylic acid

To the solution of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate(0.5 g, 1.797 mmol) in ethanol 10 ml, sodium hydroxide (aq) (5 ml, 25.00mmol) was added and stirred at room temperature for 10 hr. Reactionmixture was diluted with water (20 ml), and acidified by adding 5N HCl.Obtained white precipitates were filtered. The residue was dried byazetrope with toluene (0.38 g, 85%).

¹HNMR (400 MHz, CDCl₃) δ (ppm): 12.51 (s, 1H), 9.38 (s, 1H), 8.69 (t,1H, J=1.2 Hz), 8.41-8.39 (dd, 1H, J=1.2 and 8 Hz), 8.29 (d, 1H, J=7.6Hz), 7.79 (t, 1H, J=8 Hz), 1.64-1.13 (m, 2H), 1.45-1.42 (m, 2H).

Step-c: Synthesis of N-(1-carbamoylcyclopropyl)-3-nitrobenzamide

To the suspension of 1-(3-nitrobenzamido)cyclopropanecarboxylic acid(0.38 g, 1.519 mmol) in dichloromethane (5 ml), oxalyl chloride (0.199ml, 2.278 mmol) was added followed by DMF (0.024 ml, 0.304 mmol).Reaction mixture was stirred at room temperature for 3 hr. Aftercomplete dissolution of the compound, cold aqueous ammonia (5 ml) wasadded under cooling. Allowed and stirred the content at room temperaturefor 1 hr. concentrated the reaction mixture to remove dichloromethaneand the obtained slurry was filtered to obtain titled compound (0.28 g,74%).

Step-d: Synthesis of 3-Amino-N-(1-carbamoylcyclopropyl)benzamide

To the suspension of N-(1-carbamoylcyclopropyl)-3-nitrobenzamide (0.28g, 1.123 mmol) in methanol (5 ml), Pd—C (0.05 g) was added undernitrogen and stirred the reaction mixture under hydrogen atmosphere atroom temperature. After 2 hr, reaction mixture was filtered andconcentrated under vacuum to afford solid compound (0.2 g, 81%).

ESI-MS (m/z): 220.83 (M+1)

Intermediate xx: Synthesis of 3-Amino-N-(1-(hydroxymethyl)cyclopropyl)benzamide

Step-a: Synthesis of N-(1-(Hydroxymethyl)cyclopropyl)-3-nitrobenzamide

To the suspension of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate(0.400 g, 1.438 mmol) in tetrahydrofuran 10 ml, LiBH4 (0.063 g, 2.88mmol) was added and heated the content at 45° C. for 15 hr. Reactionmixture was quenched with saturated ammonium chloride and extracted withethyl acetate (2×10 ml). Organic layer was dried over sodium sulfate andconcentrated under vacuum which was further purified by columnchromatography eluting ethyl acetate (0-70%) in hexane (0.05 g, 14%).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 9.08 (s, 1H), 8.69 (t, 1H, J=1.6 Hz),8.38-8.35 (m, 1H), 8.30-8.27 (m, 1H), 7.75 (t, 1H, J=7.6 Hz), 4.80 (t,1H, J=6 Hz), 3.53 (d, 2H, J=5.6 Hz), 0.77-0.72 (m, 4H).

ESI-MS (m/z): 237 (M+1)

Step-b: Synthesis of 3-Amino-N-(1-(hydroxymethyl)cyclopropyl)benzamide

To the solution of N-(1-(hydroxymethyl)cyclopropyl)-3-nitrobenzamide(0.135 g, 0.571 mmol) in methanol Pd—C (50% wet) (0.015 g) was added andstirred at room temperature under hydrogen for 2 hr. Reaction mixturewas filtered through celite and concentrated to afford product (01 g,85%).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.39 (bs, 1H), 7.05-7.00 (m, 2H),6.95-6.93 (m, 1H), 6.67-6.64 (m, 1H), 5.18 (s, 2H), 4.73 (t, 1H, J=6Hz), 3.50 (d, 2H, J=5.6 Hz), 0.75-0.64 (m, 4H). GCMS: 206.98 (M+)

Intermediate xxi: Synthesis of (3-aminophenyl)(morpholino)methanone

Step-a Preparation of morpholino(3-nitrophenyl)methanone

To stirred solution of 3-nitrobenzoic acid (5 g, 29.9 mmol) in DCM: DMF(30 ml, 29:1) was added oxalyl chloride (3.14 ml, 35.9 mmol) dropwise atRT. Resulting reaction mixture was stirred for 1 h. The mixture wasconcentrated and the residue was dissolved in DCM (25 ml), the reactionmixture was cooled to 0° C. and triethylamine (6.26 ml, 44.9 mmol) andmorpholine (3.13 ml, 35.9 mmol) were added and the reaction mixture wasstirred for 1 h. The reaction mixture was concentrated under vacuum andthe residue was diluted with cold water, the solid separated out wasfiltered and washed with n-hexanes and dried under vacuum to give theproduct (4.9 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 8.32-8.29 (m, 1H), 8.23-8.22 (m, 1H),7.89-7.86 (m, 1H), 7.75 (t, J=8.00 Hz, 1H), 3.65-3.55 (m, 8H).GCMS-236.22 (M+).

Step-b Preparation of (3-aminophenyl)(morpholino)methanone

To a solution of morpholino(3-nitrophenyl)methanone (2 g, 8.47 mmol) inEthyl acetate (40 ml) was added tin(II) chloride dehydrate (7.64 g, 33.9mmol). Resulting reaction mixture was stirred at RT for 17 h. Thereaction mixture was nutralized with NaOH (2N), the mixture was filteredand the filtrate was extracted with Ethyl acetate (250 ml×2). Thecombined organic layer was washed with brine, dried over sodium sulphateand concentrated under vacuum to give the title product (1.4 g).

GCMS-206.24

Intermediate xxii: Synthesis of 2-(3-aminophenoxy)-2-methylpropanamide

Step-a: Preparation of ethyl 2-methyl-2-(3-nitrophenoxy)propanoate

To a solution of 3-nitrophenol (7.5 g, 53.9 mmol) and ethyl2-bromo-2-methylpropanoate (12.62 g, 64.7 mmol) in DMF (25 ml) was addedK₂CO₃ (14.90 g, 108 mmol). After stirring at rt for 16 hr, the reactionmixture was concentrated under vacuum. The residue was diluted withwater and extracted with ethyl acetate (3×30 ml), the combined organiclayer was washed with NaOH solution (10%, 75 mL), water (75 mL) andbrine, dried over sodium sulphate and concentrated under vacuum to givethe title product (6.7 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 7.89-7.86 (m, 1H), 7.60-7.54 (m, 2H),7.30-7.28 (m, 1H), 4.18-4.01 (m, 2H), 1.59 (s, 6H), 1.21-1.14 (m, 3H).GCMS-253.25.

Step-b: Preparation of 2-methyl-2-(3-nitrophenoxy)propanoic acid

The mixture of ethyl 2-methyl-2-(3-nitrophenoxy)propanoate (3.5 g, 13.82mmol) and LiOH.H₂O (2.320 g, 55.3 mmol) in Tetrahydrofuran (7 ml), MeOH(7 ml) and Water (7 ml) was stirred at room temperature for 4 hr. Thereaction mixture was concentrated under vacuum and the residue wasneutralised with 1N HCl, solid separated was filtered and treated withpentane to afford the title product (2.68 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 13.40 (bs, 1H), 7.86 (dd, J=1.6 & 8.0Hz, 1H), 7.60-7.56 (m, 2H), 7.31 (dd, J=2& 8.4 Hz, 1H), 1.57 (s, 6H).GCMS-225.19 (M+)

Step-c: Preparation of 2-methyl-2-(3-nitrophenoxy)propanamide

The mixture of 2-methyl-2-(3-nitrophenoxy)propanoic acid (1 g, 4.44mmol) and CDI (1.080 g, 6.66 mmol) in Tetrahydrofuran (10 ml) wasstirred at room temperature for 3 hr, ammonia (2.0 M in Methanol, 10 ml)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under vacuum and the residue wastreated with pentane to afford the title product (0.914 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 7.88-7.85 (m, 1H), 7.70-7.56 (m, 2H),7.40 (bs, 1H), 7.36-7.32 (m, 1H), 7.01 (bs, 1H), 1.49 (s, 6H).GCMS-224.21 (M+).

Step-d: Preparation of 2-(3-aminophenoxy)-2-methylpropanamide

To a stirred solution of 2-methyl-2-(3-nitrophenoxy)propanamide (0.910g, 4.06 mmol) in MeOH (15 ml) was added Pd—C (10%, 0.346 g) andtriethylsilane (6.48 ml, 40.6 mmol) (slow addition) at room temperature.The reaction mixture was stirred at same temperature for 30 min. andfiltered through celite, washed with methanol (50 ml). The Filtrate wasconcentrated under vacuum to get the crude compound. The crude compoundwas purified by flash chromatography to give the title product (0.516g).

¹HNMR (400 MHz, DMSO), δ (ppm): 7.39 (bs, 1H), 7.19 (bs, 1H), 6.86 (t,J=8.00 Hz, 1H), 6.21-6.18 (m, 1H), 6.14-6.13 (m, 1H), 6.06-6.04 (m, 1H),5.03 (s, 2H), 1.38 (s, 6H). GCMS-194.23 (M+).

Intermediate xxiii: Synthesis of(3-aminophenyl)(4-methylpiperazin-1-yl)methanone

Step-a Preparation of (4-methylpiperazin-1-yl)(3-nitrophenyl)methanone

To a solution of 3-nitrobenzoyl chloride (4.5 g, 24.25 mmol) in THF (30ml) was added 1-methylpiperazine (8.50 g, 85 mmol). The reaction wasstirred for 20 min at room temperature. The reaction mixture was dilutedwith 50 mL water and extracted with ethyl acetate (2×100 mL). Thecombined organic layer was washed with brine (50 mL). The brine was backextracted with ethyl acetate (2×50 mL) and all the organic layers werecombined, dried over magnesium sulphate, filtered, and concentratedunder vacuum give the title product (5.2 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 8.32-8.29 (m, 1H), 8.19-8.18 (m, 1H),7.86-7.84 (m, 1H), 7.77-7.72 (m, 1H), 3.64 (bs, 2H), 3.30 (bs, 2H),2.38-2.27 (m, 2H), 2.19 (s, 3H). GCMS-249.26 (M+).

Step-b Preparation of (3-aminophenyl)(4-methylpiperazin-1-yl)methanone

To a stirred solution of(4-methylpiperazin-1-yl)(3-nitrophenyl)methanone (5.5 g, 22.06 mmol) inMeOH (50 ml) was added Pd—C (10%, 0.470 g) followed by triethylsilane(14.10 ml, 88 mmol) (slow addition) at RT. The reaction mixture wasstirred at same temperature for 25 min and filtered through celite,washed with methanol (50 ml). The Filtrate was concentrated under vacuumto get the title product (4.11 g).

¹HNMR (400 MHz, DMSO), δ (ppm): 7.05 (t, J=8.0 Hz, 1H) 6.61-6.58 (m,1H), 6.53-6.52 (m, 1H), 6.45-6.43 (m, 1H), 5.25 (s, 2H), 3.55-3.32 (m,4H), 2.50-2.28 (m, 4H), 2.18 (s, 3H). GCMS-219.28 (M+).

The following intermediates given in table 1 were prepared according tothe preparation procedures depicted in the following referencesaccordingly.

TABLE-1 No. Aniline Reference xxiv

Bulletin of the Korean Chemical Society, 2011 vol. 32, #12 p. 4444-4446xxv

WO2006/129100 A1, xxvi

Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, #3 p.1169-1172 xxvii

Journal of Medicinal Chemistry, 1996, vol. 39, #26 p. 5236-5245 xxviii

Bioorganic and Medicinal Chemistry, 2008, vol. 16, #3 p. 1206-1217 xxix

U52009/82379 A1

Intermediate xxx: Synthesis of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate

Under nitrogen atmosphere, to a solution of1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione(41 g, 72.8 mmol) (Prepared as per reference WO2005121142) inacetonitrile (300 ml), triethylamine (30.4 ml, 218 mmol) andtrimethylamine hydrochloride (3.48 g, 36.4 mmol) were added slowlyfollowed by addition of p-toluensulfonylchloride (27.8 g, 146 mmol) inacetonitrile (300 ml) at 0° C., and the mixture was stirred under icecooling for 1 hr, and then at room temperature for 24 h. To the reactionmixture was added methanol (220 ml), and the mixture was stirred at roomtemperature for 1 h. The precipitated crystals were collected byfiltration, dried under vacuum to afford the titled compound (40.5 g,78%)

¹H NMR (400 MHz, DMSO-d₆) δ: 7.95 (dd, J=1.6 and 9.6 Hz, 1H), 7.84 (d,J=8.4 Hz, 2H), 7.72 (dd, J=1.2 and 8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H),7.35 (t, J=8.4 Hz, 1H), 7.23 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H),4.92 (d, J=16 Hz, 1H), 4.77 (d, J=16 Hz, 1H), 3.71 (s, 3H), 2.76 (s,3H), 2.42 (s, 3H), 1.53 (s, 3H).

MS (ESI): 717.9.

Intermediate xxxi: Synthesis of 1-(3-aminophenyl)cyclopropanecarboxamideScheme

Step a: Synthesis of 1-(3-nitrophenyl)cyclopropanecarbonitrile

A solution of 2-(3-nitrophenyl)acetonitrile (2.5 g, 15.42 mmol) and1,2-dibromoethane (1.329 ml, 15.42 mmol) in DMSO/Et₂O (1:1, 10 ml) wasadded dropwise to a suspension of NaH (1.233 g, 30.8 mmol) in DMSO(Volume: 10 ml, Ratio: 1.000), keeping the temperature at 0° C.Resulting mixture was stirred at ambient temperature for 24 h under N2atm. The reaction mixture was quenched by addition of IPA (2 ml) andwater; partitioned between water (300 ml) and EtOAc (300 ml). The aq.phase was re-extracted with EtOAc (300 ml). Combined organic layers weredried over sodium sulphate and concentrated in vacuo. The residue waspurified by flash chromatography to afford1-(3-nitrophenyl)cyclopropanecarbonitrile (1.799 g, 9.56 mmol).

¹H NMR (400 MHz, DMSO-d₆) δ 8.19-8.16 (m, 1H), 8.07-8.06 (m, 1H),7.79-7.75 (m, 1H), 7.58 (t, J=8.4 Hz, 1H), 1.91-1.84 (m, 2H), 1.56-1.48(m, 2H).

GCMS: 188.01 [M+]

Step b: Synthesis of 1-(3-nitrophenyl)cyclopropanecarboxamide

To a solution of 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.6 g, 8.50mmol) in 2-Propanol (50 ml) was added triethylbenzylammonium chloride(0.058 g, 0.255 mmol) and 25% aq KOH solution (5 ml). Resulting solutionwas stirred for 5 min. and H₂O₂(10 ml, 98 mmol, ca. 30% solution inwater) was added. Reaction mixture was heated at 50° C. for 4 h. Solventwas evaporated in vacuo and residue was suspended in water (200 ml).Precipitate was filtered and dried to obtain1-(3-nitrophenyl)cyclopropane carboxamide (1.104 g, 5.36 mmol, 63%yield).

¹H NMR (400 MHz, DMSO-d₆) δ 8.31-8.13 (m, 2H), 7.80-7.78 (m, 1H),7.64-7.60 (m, 1H), 7.11 (s, 1H), 6.58 (s, 1H), 1.42-1.35 (m, 2H),1.08-1.03 (m, 2H).

GCMS: 206.04 [M+]

Step c: Synthesis of 1-(3-aminophenyl)cyclopropanecarboxamide

Triethylsilane (7.75 ml, 48.5 mmol) was added dropwise to a suspensionof 1-(3-nitrophenyl)cyclopropanecarboxamide (1 g, 4.85 mmol) and Pd/C(10%, 250 mg) in MeOH (20 ml). Resulting suspension was stirred at RTfor 20 min. and filtered through celite. The filtrate was evaporated andtriturated in hexane to obtain the crystals which were collected byfiltration to afford the title compound (0.68 g).

¹H NMR (400 MHz, DMSO-d₆) δ 7.04 (brs, 1H), 6.98 (t, J=8.0 Hz, 1H),6.60-6.56 (m, 1H), 6.49-6.45 (m, 2H), 5.90 (brs, 1H), 5.09 (s, 2H),1.26-1.23 (m, 2H), 0.88-0.85 (m, 2H).

GCMS: 176.07 [M+]

Example-1: Synthesis of3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide(Compound 1)

Step-1: Synthesis of3-(3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl) propanamide (1b)

To a stirred solution of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzene sulfonate (xxx) (2 gm, 2.79 mmol) in DMA (5 ml) wasadded 2,6-lutidine (0.597 g, 5.57 mmol) and 3-(3-aminophenyl)propanamide(intermediate xxvi) (0.915 gm, 5.57 mmole). The reaction mixture washeated at 130° C. for 16 h. The reaction mixture was cooled to roomtemperature and added water until a solid precipitate was obtained. Thesolid was filtered, washed with water and small amount of MeOH. Thesolid was purified by silica gel column chromatography, eluting withDCM: Methanol (9:1), to yield the titled compound (1b) (1.7 g)[m/z=710.20 (M+1)].

¹HNMR (400 MHz, DMSO-d₆) δ 10.2 (s, 1H), 7.97 (dd, 2.0 and 9.6 Hz, 1H),7.75 (dd, 1.2 and 8.4 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.28 (d, J=8.8 Hz,3H), 7.20 (t, J=8 Hz, 1H), 6.86 (m, 3H), 6.76 (m, 3H), 5.00 (m, 2H),3.70 (s, 3H), 2.75 (m, 5H), 2.33 (t, J=7.2 Hz, 2H), 1.50 (s, 3H).

Step-2: Synthesis of3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (1c)

To a solution of3-(3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)propanamide (1b) (1.7 gm, 2.396 mmol) in THF (8 ml) was added sodiummethoxide (30% solution in MeOH) (0.431 mg, 2.396 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 2 hr and quenchedby addition of 2N HCl solution. The resulting mixture was concentratedunder vacuum and residue was re-crystallized in IPA, methanol and waterto yield the titled compound (Ic) (1.5 g, 88%) [m/z=710.20 (M+1)].

¹H NMR (400 MHz, DMSO-d₆) δ 11.11 (s, 1H), 7.78 (dd, J=2 Hz and 10.4 Hz,1H), 7.52 (dd, J=1.2 Hz and 9.6 Hz, 1H), 7.35 (t, J=8 Hz, 2H), 7.22 (m,5H), 6.98 (t, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 2H), 6.79 (s, 1H), 4.96(s, 2H), 3.67 (s, 3H), 3.14 (s, 3H), 2.78 (m, 2H), 2.42 (m, 2H), 1.22(s, 3H).

Step-3: Synthesis of3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide(1)

Aluminium chloride (2.82 g, 21.14 mmol) was added in small portions to asolution of3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide(1c) (1.500 g, 2.114 mmol) in anisole (15 ml). The resulting reactionmixture was stirred at room temperature for 24 h, then quenched byaddition of MeOH (15 ml) and 2N HCl (0.5 ml). The resulting mixture wasconcentrated under vacuum and the residue thus obtained was purified bysilica gel column chromatography to yield the titled compound (1) (0.450g, 44%) [m/z=590.1 (M+1)].

¹HNMR (400 MHz, DMSO-d₆) δ 11.57 (s, 1H), 11.22 (s, 1H), 7.78 (dd,J=2&10.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.31(brs, 1H), 7.26 (brs, 1H), 7.24-7.21 (m, 2H), 6.94 (t, J=8.4 Hz, 1H),6.78 (brs, 1H), 3.06 (s, 3H), 2.82 (t, J=7.6 Hz, 2H), 2.36 (t, J=6.4 Hz,2H), 1.19 (s, 3H).

The compounds given below in Table 2: were prepared by procedure similarto the one described above in Example 1 with the above statedintermediates with appropriate variations in reactants, reactionconditions and quantities of reagents.

TABLE 2 Cmpd. No. Intermed. No. Name Analytical data 2 xxivN-cyclopropyl-3-(5-((2-fluoro- ¹H NMR (400 MHz, DMSO-d₆) δ4-iodophenyl)amino)-6,8- 11.62 (s, 1H), 11.21 (s, 1H), 8.52 (d,dimethyl-2,4,7-trioxo-3,4,6,7- 1H, J = 4 Hz), 7.86-7.83 (m, 1H), 7.80-tetrahydropyrido[4,3- 7.77 (m, 2H), 7.58-7.51 (m, 3H), 6.96d]pyrimidin-1(2H)- (t, 1H, J = 8.8 Hz), 3.06 (s, 3H), 2.86- yl)benzamide2.80 (m, 1H), 1.16 (s, 3H), 0.70-0.68 (m, 2H), 0.58-0.57 (m, 2H) MS: m/z602.1 (M + 1). 3 i 1-(3-(azetidine-1- ¹H NMR (400 MHz, DMSO-d₆), δcarbonyl)phenyl)-5-((2-fluoro- 11.59 (s, 1H), 11.18 (s, 1H), 7.79 (dd,4-iodophenyl)amino)-6,8- J = 1.6 and 10.0 Hz, 1H), 7.62-7.59 dimethylpyrido[4,3- (m, 2H), 7.56-7.52 (m, 3H), 6.96 (t, d]pyrimidine- 1H, J =8.8 Hz), 4.28-4.26 (m, 2H), 2,4,7(1H,3H,6H)-trione 4.06-4.02 (m, 2H),3.06 (s, 3H), 2.27- 2.23 (m, 2H), 1.18 (s, 3H). MS: m/z 602.1 (M + 1). 4ii N-cyclopropyl-2-(3-(5-((2- ¹H NMR (400 MHz, DMSO-d₆), δfluoro-4-iodophenyl)amino)- 11.58 (s, 1H), 11.22 (s, 1H), 8.14 (d,6,8-dimethyl-2,4,7-trioxo- 1H, J = 4 Hz), 7.79 (dd, J = 1.6 and3,4,6,7-tetrahydropyrido[4,3- 10.0 Hz, 1H), 7.55-7.53 (m, 1H),d]pyrimidin-1(2H)- 7.39-7.36 (m, 1H), 7.28-7.21 (m, 3H),yl)phenyl)acetamide 6.93 (t, 1H, J = 8.8 Hz), 3.38 (s, 2H), 3.05 (s,3H), 2.60-2.54 (m, 1H), 1.17 (s, 3H), 0.59-0.57 (m, 2H), 0.36-0.35 (m,2H). MS: m/z 615.9 (M + 1). 5 xxv 2-(3-(5-((2-fluoro-4- ¹H NMR (400 MHz,DMSO-d₆), δ iodophenyl)amino)-6,8- 11.57 (s, 1H), 11.21 (s, 1H), 8.07(brs, dimethyl-2,4,7-trioxo-3,4,6,7- 1H), 7.80-7.77 (m, 1H), 7.56-7.53(m, tetrahydro pyrido[4,3- 2H), 7.40-7.36 (m, 2H), 7.04-7.01 (m,d]pyrimidin-1(2H)- 3H), 6.94 (t, 1H, J = 8 Hz), 4.48 (s, 2H),yl)phenoxy)-N- 3.06 (s, 3H), 2.64 (s, 3H), 1.26 (s, 3H). methylacetamideMS: m/z 606.0 (M + 1). 6 iii N-cyclopropyl-2-(3-(5-((2- ¹HNMR (400 MHz,DMSO-d6), δ fluoro-4-iodophenyl)amino)- 11.58 (s, 1H), 11.20 (s, 1H),8.15 (d, J = 6,8-dimethyl-2,4,7-trioxo- 4 Hz, 1H), 7.79 (dd, J = 1.6 and10.0 3,4,6,7-tetrahydropyrido[4,3- Hz, 1H), 7.55 (d, J = 8 Hz, 1H), 7.37d]pyrimidin-1(2H)- (t, J = 8.8 Hz, 1H), 7.02-6.92 (m, 4H),yl)phenoxy)acetamide 4.45 (s, 2H), 3.06 (s, 3H), 2.69-2.65 (m, 1H), 1.23(s, 3H), 0.64-0.59 (m, 2H), 0.48-0.46 (m, 2H). MS: m/z 632.0 (M + 1). 7xxi 5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ iodophenyl)amino)-6,8-11.61 (s, 1H), 11.18 (s, 1H), 7.80 (dd, dimethyl-1-(3-(morpholine-4- J =2 & 10.4 Hz, 1H), 7.56-7.43 (m, carbonyl)phenyl) pyrido[4,3- 5H), 6.96(t, J = 8.8 Hz, 1H), 3.61-3.39 d]pyrimidine- (m, 6H), 3.34-3.32 (m, 2H),3.06 (s, 2,4,7(1H,3H,6H)-trione 3H), 1.21 (s, 3H). MS: m/z 631.9 (M +1). 8 v 1-(3-(1,1- ¹HNMR (400 MHz, DMSO-d6), δ dioxidothiomorpholine-4-11.64 (s, 1H), 11.18 (s, 1H), 7.79 (dd, carbonyl)phenyl)-5-((2-fluoro- J= 2 & 10.4 Hz, 1H), 7.60-7.49 (m, 4-iodophenyl)amino)-6,8- 5H), 6.96 (t,J = 8.8 Hz, 1H), 4.03-4.01 dimethylpyrido[4,3- (m, 2H), 3.68 (brs, 2H),3.29-3.27 (m, d]pyrimidine- 4H), 3.06 (s, 3H), 1.21 (s, 3H).2,4,7(1H,3H,6H)-trione MS: m/z 680.0 (M + 1) 9 vi 2-(3-(5-((2-fluoro-4-¹HNMR (400 MHz, DMSO-d6), δ iodophenyl)amino)-6,8- 11.57 (s, 1H), 11.26(s, 1H), 7.78 (dd, dimethyl-2,4,7-trioxo-3,4,6,7- J = 2 & 10.4 Hz, 1H),7.55 (dd, J = 1.2 & tetrahydro pyrido[4,3- 8.4 Hz, 1H), 7.43-7.37 (m,2H), 7.29- d]pyrimidin-1(2H)-yl)phenyl)- 7.26 (m, 2H), 6.98-6.91 (m,3H), 3.06 2-methylpropanamide (s, 3H), 1.43 (s, 6H), 1.16 (s, 3H). MS:m/z 603.9 (M + 1). 10 viii 2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz,DMSO-d6), δ iodophenyl)amino)-6,8- 11.57 (s, 1H). 11.21 (s, 1H), 7.79(dd, dimethyl-2,4,7-trioxo-3,4,6,7- J = 1.6 & 10 Hz, 1H), 7.55 (dd, J =1.2 & tetrahydro pyrido[4,3- 8.4 Hz, 1H), 7.39 (m, 1H), 7.29-7.19d]pyrimidin-1(2H)-yl)phenyl)- (m, 3H), 6.94 (t, J = 8.8 Hz, 1H), 3.73N,N-dimethylacetamide (s, 2H), 3.06 (s, 3H), 2.99 (s, 3H), 2.82 (s, 3H),1.21 (s, 3H), MS: m/z 604.0 (M + 1). 11 vii2,2-difluoro-2-(3-(5-((2-fluoro- ¹HNMR (400 MHz, DMSO-d6), δ4-iodophenyl)amino)-6,8- 11.63 (s, 1H), 11.22 (s, 1H), 8.40 (brs,dimethyl-2,4,7-trioxo-3,4,7,8- 1H), 8.07 (brs, 1H), 7.79 (dd, J = 1.6 &tetrahydropyrido[2,3- 10.4 Hz, 1H), 7.64-7.54 (m, 5H), 6.95d]pyrimidin-1(2H)- (t, J = 8.8 Hz, 1H), 3.06 (s, 3H), 1.13 (s,yl)phenyl)acetamide 3H). MS: m/z 612.0 (M + 1). 12 xixN-(1-Carbamoylcyclopropyl)- ¹HNMR (400 MHz, DMSO-d6), δ3-(5-((2-fluoro-4- 11.62 (s, 1H), 11.21 (s, 1H), 8.98 (s,iodophenyl)amino)-6,8- 1H), 7.93 (d, 1H, J = 7.6 Hz), 7.82-dimethyl-2,4,7-trioxo-3,4,6,7- 7.77 (m, 2H), 7.59-7.52 (m, 2H), 7.36tetrahydropyrido[4,3- (s, 1H), 7.03 (s, 1H), 6.96 (t, 1H, J =d]pyrimidin-1(2H)- 8.8 Hz), 5.76 (s, 1H), 3.06 (s, 3H), yl)benzamide1.21 (s, 3H), 0.98-0.92 (m, 2H), 0.87- 0.83 (m, 2H). MS: m/z 645.0 (M +1). 13 xiv 3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δiodophenyl)amino)-6,8- 11.63 (s, 1H), 11.22 (s, 1H), 8.41 (d,dimethyl-2,4,7-trioxo-3,4,6,7- 1H, J = 7.6 Hz), 7.91-7.88 (m, 1H), 7.83tetrahydropyrido [4,3- (s, 1H), 7.79 (dd, 1H, J = 2 and 8.4 Hz),d]pyrimidin-1(2H)-yl)-N- 7.59-7.53 (m, 3H), 6.96 (t, 1H, J = 8.8(tetrahydro-2H-pyran-4- Hz), 4.01-3.96 (m, 1H), 3.88 (dd, 2H,yl)benzamide J = 2 and 11.2 Hz), 3.38 (dd, 2H, J = 2 and 12 Hz), 3.06(s, 3H), 1.78-1.74 (m, 2H), 1.62-1.55 (m, 2H), 1.18 (s, 3H). MS: m/z646.0 (M + 1). 14 xiii 2-(3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δiodophenyl)amino)-6,8- 11.58 (s, 1H), 11.23 (s, 1H), 7.79 (dd,dimethyl-2,4,7-trioxo-3,4,6,7- 1H, J = 2 and 8.4 Hz), 7.55 (dd, 1H, J =tetrahydro pyrido[4,3- 2 and 8.4 Hz), 7.47-7.39 (m, 3H),d]pyrimidin-1(2H)-yl)phenyl)- 7.36-7.32 (m, 2H), 7.22 (bs, 1H), 6.942-hydroxyacetamide (t, 1H, J = 8.8 Hz), 6.15 (bs, 1H), 4.88 (d, 1H, J =4.8 Hz), 3.06 (s, 3H), 1.16 (s, 3H). MS: m/z 592.0 (M + 1). 15 ix3-(3-(5-((2-fluoro-4- ¹H NMR (400 MHz, DMSO-d₆) δ iodophenyl)amino)-6,8-11.56 (s ,1H), 11.21 (s, 1H), 7.80-7.75 dimethyl-2,4,7-trioxo-3,4,6,7-(m, 2H), 7.54 (d, 1H, J = 8 Hz), 7.36 tetrahydro pyrido[4,3- (t, J = 7.6Hz, 1H), 7.24-7.19 (m, 3H), d]pyrimidin-1(2H)-yl)phenyl)- 6.94 (t, 1H, J= 8 Hz ), 3.05 (s, 3H), N-methylpropanamide 2.84-2.81 (m, 2H), 2.50 (s,3H), 2.37- 2.35 (m,2H), 1.17 (s, 3H). MS: m/z 602.9 (M + 1). 16 xxvii2-(3-(5-((2-fluoro-4- ¹H NMR (400 MHz, DMSO-d₆) δ iodophenyl)amino)-6,8-11.57 (s, 1H), 11.21 (s, 1H), 7.79 (dd, dimethyl-2,4,7-trioxo-3,4,6,7-1H, J = 1.6 and 10.4 Hz), 7.57-7.53 (m, tetrahydro pyrido[4,3- 2H), 7.41(brs, 1H), 7.37 (t, J = 8.0 d]pyrimidin-1(2H)- Hz), 7.04-7.00 (m, 3H),6.94 (t, yl)phenoxy)acetamide J = 8 Hz, 1H,), 4.43 (s, 2H), 3.06 (s,3H), 1.26 (s, 3H). MS: m/z 591.08 (M + 1). 17 iv1-(3-(1,1-dioxidothiazolidine- ¹HNMR (400 MHz, DMSO-d6), δ3-carbonyl)phenyl)-5-((2- 11.62 (s, 1H), 11.17 (s, 1H), 7.78fluoro-4-iodophenyl)amino)- (dd, 1H, J = 2.0 and 10.4 Hz), 7.60-7.546,8-dimethylpyrido[4,3- (m, 5H), 6.96 (t, 1H J = 8.4 Hz), 4.67d]pyrimidine- (bs, 2H), 3.99 (bs, 2H), 3.50 (t, 2H2,4,7(1H,3H,6H)-trione J = 7.4 Hz), 3.06 (s, 3H), 1.21 (s, 3H). 18 x5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ iodophenyl)amino)-1-(3-(4-11.60 (s, 1H), 11.17 (s, 1H), 7.78 hydroxypiperidine-1- (dd, 1H, J = 2Hz, J = 10.4 Hz), 7.56-7.49 carbonyl)phenyl)-6,8- (m, 3H), 7.47-7.38 (m,2H), 6.95 (t, dimethylpyrido[4,3- 1H, J = 8.8 Hz), 4.81 (d, 1H, J = 3.6d]pyrimidine- Hz), 4.67 (bs, 2H), 4.01-3.99 (m, 2,4,7(1H,3H,6H)-trione1H0, 3.74-3.72 (m, 1H), 3.51-3.48 (m, 1H), 3.18-3.16 (m, 2H), 3.06 (s,3H), 1.78-1.67 (m, 2H), 1.37-1.23 (m, 2H), 1.21 (s, 3H). MS: m/z 645.8(M + 1). 19 xviii N-cyclopropyl-3-(3-(5-((2- ¹H NMR (400 MHz, DMSO-d₆)δ: fluoro-4-iodophenyl)amino)- 11.35 (brs, 2H), 7.88 (d, J = 4.0 Hz,1H), 6,8-dimethyl-2,4,7-trioxo- 7.75 (d, J = 9.2 Hz, 1H), 7.52 (d,3,4,6,7-tetrahydropyrido[4,3- J = 8.4 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H),d]pyrimidin-1(2H)- 7.21 (t, J = 7.2 Hz, 2H), 7.17 (s, 1H),yl)phenyl)propanamide 6.92 (t, J = 8.4 Hz, 1H), 3.07 (s, 3H), 2.82 (t, J= 8.0 Hz, 2H), 2.58-2.53 (m, 1H), 2.32 (t, J = 7.2 Hz, 2H), 1.18 (s,3H), 0.58-0.53 (m, 2H), 0.33-0.29 (m, 2H). MS: m/z 630 (M + 1). 20 xxii2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ iodophenyl)amino)-6,8-11.56 (s, 1H), 11.20 (s, 1H), 7.79 (dd, dimethyl-2,4,7-trioxo-3,4,6,7- J= 1.6 & J = 10.0 Hz, 1H), 7.61 (brs, tetrahydro pyrido[4,3- 1H),7.56-7.54 (m, 1H), 7.35 (t, J = 7.6 d]pyrimidin-1(2H)- Hz 1H), 7.29(brs, 1H), 7.04-7.02 (m, yl)phenoxy)-2- 1H), 6.96-6.92 (m, 3H) 3.06 (s,3H), methylpropanamide 1.43 (s, 6H), 1.26 (s, 3H), MS: m/z 619.6 (M +1). 21 xxiii 5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δiodophenyl)amino)-6,8- 11.60 (s, 1H), 11.18 (s, 1H), 7.79 (d,dimethyl-1-(3-(4- J = 10.4 Hz, 1H), 7.56-7.40 (m, 5H),methylpiperazine-1-carbonyl) 6.95 (t, J = 8.4 Hz, 1H), 3.61-3.37 (m,phenyl)pyrido[4,3- 4H), 3.06 (s, 3H), 2.35-2.29 (m, 4H), d]pyrimidine-2.19 (s, 3H), 1.21 (s, 3H) 2,4,7(1H,3H,6H)-trione MS: m/z 644.7 (M + 1).77 xxxi 1-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δiodophenyl)amino)-6,8- 11.57 (s, 1H), 11.12 (s, 1H), 7.78 (dd, dimethyl-2,4,7-trioxo-3,4,6,7- J = 1.6 and 8.8 Hz, 1H), 7.55 (dd, J =tetrahydropyrido [4,3-d] pyrimidin- 0.8 and 8.4 Hz, 1H), 7.45-7.38 (m,1(2H)-yl)phenyl) 2H), 7.35-7.32 (m, 2H), 7.17 (brs,cyclopropanecarboxamide 1H), 6.95 (t, J = 8.4 Hz, 1H), 6.09 (brs, 1H),3.06 (s, 3H), 1.34 (brs 2H), 1.21 (s, 3H), 0.98 (brs 2H). MS: m/z 601.9(M + 1)

Example-2: Synthesis of5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(22)

Step-1: Synthesis of3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoicacid (2b)

To a stirred solution of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzene sulfonate (2a) (2.0 gm, 2.79 mmol) in DMA (5 ml) wasadded 2,6-lutidine (0.98 ml, 8.36 mmol) and 3-aminobenzoic acid (1.147gm, 8.36 mmol). The reaction mixture was heated at 130° C. for 16 h. Thereaction mixture was cooled to room temperature and water was addedfollowed by extraction with Ethyl acetate. The organic phase was driedover sodium sulphate. The solvent was evaporated in vacuo and theresidual solid was purified by silica gel column chromatography, elutingwith Hexane: Ethyl acetate (1:1), to yield the titled compound (2b) (1.4g)

¹H NMR (400 MHz, DMSO-d₆) δ 13.02 (s, 1H), 10.24 (s, 1H), 7.96 (dd,J=1.2 and 8.0 Hz, 1H), 7.74 (dd, J=1.2 and 8.4 Hz, 1H), 7.57 (d, J=8.0Hz, 1H), 7.41-7.38 (m, 2H), 7.29-7.22 (m, 3H), 6.86 (d, J=8.8 Hz, 2H),5.04-4.94 (m, 2H), 3.69 (s, 3H), 2.77 (s, 3H), 1.52 (s, 3H). [m/z=682.5(M+1)].

Step-2: Synthesis of1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione(2c)

To a stirred solution of3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoicacid (2b) (800 mg, 1.172 mmol) in THF (5 ml) was added EDC.HCl (494 mg,2.58 mmol), HOBT (395 mg, 2.58 mmol), DIPEA (0.819 ml, 4.69 mmol) andpyrrolidin-3-ol hydrochloride (290 mg, 2.35 mmol). The reaction mixturewas stirred at room temperature under N2 atm for 6 h. The reactionmixture was then partitioned between water and ethyl acetate. Organicphase was removed, washed with brine and dried over sodium sulphate. Thesolvent was evaporated in vacuop to afford crude1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione(2c) (550 mg) which was carried forward for the next step withoutfurther purification.

¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 7.97 (dd, J=1.6 and 9.6 Hz,1H), 7.74 (dd, J=1.2 and 8.4 Hz, 1H), 7.40-7.34 (m, 2H), 7.28 (d, J=8.4Hz, 2H), 7.11 (t, J=6.8 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.97 (brs, 1H),6.86 (d, J=8.8 Hz, 2H), 5.04-4.93 (m, 3H), 4.31-4.21 (m, 1H), 3.70 (s,3H), 3.55-3.48 (m, 2H), 3.41-3.35 (m, 1H), 2.76 (s, 3H), 1.94-1.78 (m,2H), 1.53 (s, 3H), 1.26-1.23 (m, 1H). [m/z=752.0 (M+1)].

Step-3: Synthesis of5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(2d)

To a stirred solution of1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione(550 mg, 0.732 mmol) in THF (2 ml) and Methanol (1 ml), was added K₂CO₃(202 mg, 1.464 mmol) at RT. The reaction mixture was stirred at roomtemperature for 3 h under N2 atm. The solvents were evaporated in vacuoand the residue was suspended in dilute HCl (10 ml). The suspension wasextracted several times with ethyl acetate. The combined organic phasewas washed with brine and dried over sodium sulphate. The solvent wasevaporated in vacuo to afford crude5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(2d) (500 mg) which was carried forward for the next step withoutfurther purification.

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.78 (dd, J=2.0 and 10.4 Hz,1H), 7.58-7.53 (m, 5H), 7.25 (d, J=8.8 Hz, 2H), 6.99 (t, J=8.8 Hz, 1H),6.84 (d, J=8.8 Hz, 2H), 5.03-4.96 (m, 3H), 4.32-4.24 (m, 1H), 3.70 (s,3H), 3.58-3.51 (m, 2H), 3.13-3.12 (m, 1H), 3.09 (s, 3H), 1.95-1.91 (m,1H), 1.83-1.80 (m, 1H), 1.22 (s, 3H), 1.19-1.15 (m, 1H). [m/z=751.80(M+1)].

Step-4: Synthesis of5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione

Aluminium chloride (0.887 g, 6.65 mmol) was added in small portions to asolution of crude5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(2d) (0.500 g, 0.665 mmol) in Anisole (5 ml). The resulting reactionmixture was stirred at room temperature for 16 h, which was thenquenched by addition of MeOH (15 ml) and 2N HCl (0.5 ml). The resultingmixture was concentrated under vacuum and the residue thus obtained waspurified by silica gel column chromatography to yield the titledcompound (22) (0.13 g)

¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H), 11.19 (s, 1H), 7.78 (dd,J=1.6 and 10.4 Hz, 1H), 7.56-7.51 (m, 5H), 6.96 (t, J=8.4 Hz, 1H), 5.0(brs, 1H), 4.32-4.24 (m, 1H), 3.60-3.51 (m, 2H), 3.41-3.37 (m, 1H), 3.06(s, 3H), 1.95-1.92 (m, 1H), 1.83-1.75 (m, 1H), 1.25 (s, 3H), 1.24-1.21(m, 1H). [[m/z=631.50 (M+1)].

Example-3: Synthesis of5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(Compound 23)

Step-1: Synthesis of methyl3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate(3b)

To a stirred solution of1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzene sulfonate (3a) (8.70 gm, 12.13 mmol) in DMA (10 ml) wasadded 2,6-lutidine (3.5 ml, 30.3 mmol) and methyl 3-aminobenzoate (5.5g, 36.4 mmol). The reaction mixture was heated at 130° C. for 16 h. Thereaction mixture was cooled to room temperature and water was addedfollowed by extraction with Ethyl acetate. The organic phase was driedover sodium sulphate. The solvent was evaporated in vacuo and theresidual solid was purified by silica gel column chromatography, elutingwith Hexane: Ethyl acetate, to yield the titled compound (3b) (4.2 g)

¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 7.97 (d, J=9.6 Hz, 1H), 7.75(d, J=8.4 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.48-7.37 (m, 3H), 7.30-7.23(m, 3H), 6.85 (d, J=8.4 Hz, 2H), 5.04-4.94 (m, 2H), 3.84 (s, 3H), 3.70(s, 3H), 2.78 (s, 3H), 1.53 (s, 1H). [m/z=630.7 (M+1)].

Step-2: Synthesis of methyl3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate(3c)

To a stirred solution of methyl3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate(3b) (3.20 g, 4.59 mmol) in THF (5 ml) and Methanol (10 ml), was addedK₂CO₃ (2.54 g, 18.38 mmol) at RT. The reaction mixture was stirred atroom temperature for 3 h under N₂ atm. The solvents were evaporated invacuo and the residue was suspended in water, the precipitated productwas collected by filtration and dried under high vacuum to afford thetitled compound (3c), (2.1 g). The crude product was carried forward forthe next step without further purification.

[m/z=697.0 (M+1)].

Step-3: Synthesis of3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoicacid (3d)

A mixture of methyl3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate(0.500 g, 0.718 mmol) and LiOH.H₂O (0.120 g, 2.87 mmol) in THF (5.0 ml),MeOH (5.0 ml), and Water (5.0 ml) was stirred at room temperature for 17h. The solvents were evaporated in vacuo and the residue was acidifiedwith 1 N HCl until solid was precipitated. The product was collected byfiltration and triturated in pentane, drying of this solid under vacuumafforded titled compound (3d), (0.312 g, 63.7%); which was carriedforward for the next step without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 11.09 (s, 1H), 7.98-7.96 (m,2H), 7.79 (dd, J=1.6 and 10.4 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.62-7.53(m, 2H), 7.25 (d, J=8.8 Hz, 2H), 7.00 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.8Hz, 2H), 3.70 (s, 3H), 3.09 (s, 3H), 1.17 (s, 3H). [m/z=683.0 (M+1)].

Step-4: Synthesis of tert-butyl4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate(3e)

To a stirred solution of3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoicacid (1 g, 1.465 mmol), EDC (0.421 g, 2.198 mmol), HOBT (0.337 g, 2.198mmol) and tert-butyl piperazine-1-carboxylate (0.409 g, 2.198 mmol) inTHF (5 ml); cooled to 0° C., was added Hunig's base (0.512 ml, 2.93mmol). The resulting mixture was stirred under N2 atm for 2 h at roomtemperature. The solvent was evaporated in vacuo and the residue waspartitioned between ethyl acetate (25 ml) and water (25 ml). The organicphase was separated and aq. phase was re-extracted with ethyl acetate.The combined organic layers were dried over sodium sulphate andevaporated in vacuo to obtain crude product, which was carried forwardfor the next step without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 7.78 (dd, J=2.0 and 6.0 Hz, 1H), 7.58-7.46(m, 5H), 7.28 (d, J=8.8 Hz, 2H), 7.01 (t, J=8.4 Hz, 1H), 6.86 (d, J=8.8Hz, 2H), 4.96 (s, 2H), 3.72 (s, 3H), 3.58-3.30 (m, 6H), 3.09 (s, 3H),1.40 (s, 9H), 1.17 (s, 3H).

Step-5: Synthesis of5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(23)

Aluminium chloride (1.57 g, 11.76 mmol) was added in small portions to asolution of crude tert-butyl4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate(1 g, 1.176 mmol) in Anisole (5 ml). The resulting reaction mixture wasstirred at room temperature for 17 h, methanol (10 ml) was addeddropwise and the resulting mixture was concentrated in vacuo. Aq.ammonia was added to the resulting residue and the reaction mixture wasextracted several times with DCM. The combined organic phase was washedwith brine and dried over sodium sulphate. The solvent was evaporated invacuo and the residue was purified by column chromatography over neutralalumina to afford the titled compound (23) (0.113 g).

¹HNMR (400 MHz, DMSO-d6), δ (ppm): 7.78 (dd, J=2 & 10.4 Hz, 1H),7.56-7.39 (m, 5H), 6.95 (t, J=8.8 Hz, 1H), 3.54-3.25 (m, 4H), 3.06 (s,3H), 2.73-2.64 (m, 4H), 1.21 (s, 3H). [m/z=630.4 (M+1)].

Example 4:1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(Compound 24)

Step-1: Synthesis of5-((3-(azetidine-1-carbonyl)phenyl)amino)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione.(4b)

In a sealed tube3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl4-methylbenzenesulfonate (4a) (0.5 g, 0.78 mmol),(3-aminophenyl)(azetidin-1-yl)methanone (intermediate 1) (0.27 g, 1.56mmol) were taken to the mixture DMA (2 ml) and 2,6-lutidine (0.42 mg,3.92 mmol) were added and the mixture was heated at 130° C. for 16 hrunder nitrogen atmosphere. After completion of the reaction, thereaction mixture was poured into ice cold water, the separated solid wasfiltered off and washed with water and dried under vacuum. The crudesolid was purified by column chromatography to yield the titled compound(0.11 g).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 10.13 (s, 1H), 7.95 (dd, J=1.6 & 9.2Hz, 1H), 7.75-7.70 (m, 1H), 7.37 (t, J=8 Hz, 1H), 7.27 (t, J=8 Hz, 1H),7.21 (d, J=7.6 Hz, 1H), 7.12-7.06 (m, 2H), 4.27 (t, J=7.2 Hz, 2H), 4.02(t, J=7.6 Hz, 2H), 2.74 (s, 3H), 2.67-2.64 (m, 1H), 2.28-2.21 (m, 2H),1.52 (s, 3H), 1.01-0.99 (m, 2H), 0.72-0.63 (m, 2H). [m/z=642.1 (M+1)].

Step-2: Synthesis of1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione(24)

5-((3-(azetidine-1-carbonyl)phenyl)amino)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione(4b) (0.11 g, 0.17 mmol) was taken in tetrahydrofuran (3 ml) at roomtemperature, sodium methoxide (25% in MeOH, 371 mg, 1.71 mmol) was addedand the reaction mixture was stirred at the same temperature for 1 hrunder nitrogen atmosphere. The progress of the reaction was monitored byHPLC. After complete consumption of the substrate, the reaction mixturewas diluted with HCl (2 mL, 2 N) and concentrated under vacuum. To theresidue DCM (20 ml) was added, the organic layer was dried over sodiumsulphate and concentrated under vacuum to give the crude compound whichwas purified by column chromatography to give the title product (0.09g).

¹H NMR (400 MHz, DMSO-d₆) δ (ppm): 11.05 (s, 1H), 7.80-7.77 (m, 1H),7.63-7.59 (m, 2H), 7.58-7.51 (m, 3H), 6.96-6.92 (m, 1H), 4.27-4.21 (m,2H), 4.06-4.02 (m, 2H), 3.07 (s, 3H), 2.62-2.59 (m, 1H), 2.27-2.23 (m,2H), 1.18 (s, 3H), 0.97-0.95 (m, 2H), 0.72-0.60 (m, 2H).ESI-MS:[m/z=642.1 (M+1)].

The compounds given below in Table 3: were prepared by procedure similarto the one described above in Example 4 with the above statedintermediates and with appropriate variations in reactants, reactionconditions and quantities of reagents.

TABLE 3 Cmpd. No. Intermed. No. Name Analytical data 25 iiiN-cyclopropyl-2-(3-(3- ¹HNMR (400 MHz, DMSO-d6), δ 11.06cyclopropyl-5-((2-fluoro-4- (s, 1H), 8.15 (d, J = 4 Hz, 1H), 7.79 (dd, J= iodophenyl)amino)-6,8- 1.6 and 10.4 Hz, 1H), 7.55 (d, J = 8.4dimethyl-2,4,7-trioxo- Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.99- 3,4,6,7-6.91 (m, 4H), 4.44 (s, 2H), 3.07 (s, 3H), tetrahydropyrido[4,3-2.68-2.51 (m, 2H), 1.25 (s, 3H), 0.96- d]pyrimidin-1(2H)- 0.95 (m, 2H),0.68-0.59 (m, 4H), 0.48- yl)phenoxy)acetamide 0.44 (m, 2H). MS: m/z672.0 (M + 1). 26 xxviii 2-(3-(3-cyclopropyl-5-((2- ¹HNMR (400 MHz,DMSO-d6), δ 11.08 fluoro-4- (brs, 1H), 7.78-7.76 (m, 1H), 7.52-7.49iodophenyl)amino)-6,8- (m, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.28-dimethyl-2,4,7-trioxo- 7.23 (m, 3H), 6.92-6.89 (m, 2H), 3.40 (s,3,4,6,7- 2H), 3.08 (s, 3H), 2.59 (brs, 1H), 1.18 (s,tetrahydropyrido[4,3- 3H), 0.95-0.93 (m, 2H), 0.65 (brs, 2H).d]pyrimidin-1(2H)- MS: m/z 616.1 (M + 1). yl)phenyl)acetamide 27 xxix3-cyclopropyl-5-((2-fluoro- ¹HNMR (400 MHz, DMSO-d6), δ 11.044-iodophenyl)amino)-6,8- (s, 1H), 7.79 (dd, J = 1.6 and 10.4 Hz,dimethyl-1-(3-(pyrrolidine-1- 1H), 7.56-7.45 (m, 5H), 6.94 (t, J = 8.8carbonyl)phenyl)pyrido[4,3- Hz, 1H), 3.47-3.29 (m, 4H), 3.01 (s, 3H),d]pyrimidine- 2.66-2.63 (m, 1H), 1.88-1.74 (m, 4H),2,4,7(1H,3H,6H)-trione 1.21 (s, 3H), 0.98-0.93 (m, 2H), 0.69- 0.65 (m,2H). MS: m/z 656.0 (M + 1). 28 vi 2-(3-(3-cyclopropyl-5-((2- ¹HNMR (400MHz, DMSO-d6), δ 11.10 fluoro-4- (s, 1H), 7.79 (d, J = 10.4 Hz, 1H),7.55 (d, iodophenyl)amino)-6,8- J = 8.8 Hz, 1H), 7.43-7.36 (m, 2H),7.28- dimethyl-2,4,7-trioxo- 7.24 (m, 2H), 6.97-6.89 (m, 3H), 3.11 (s,3,4,6,7- 3H), 2.62-2.61 (m, 1H), 1.43 (s, 6H), tetrahydropyrido[4,3-1.18 (s, 3H), 0.96-0.95 (m, 2H), 0.68 d]pyrimidin-1(2H)- (brs, 2H).yl)phenyl)-2- MS: m/z 644.1 (M + 1). methylpropanamide 29 viii2-(3-(3-cyclopropyl-5-((2- ¹HNMR (400 MHz, DMSO-d6), δ 11.07 fluoro-4-(s, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.55 (d, iodophenyl)amino)-6,8- J =8.4 Hz, 1H), 7.38 (m, 1H), 7.27-7.19 dimethyl-2,4,7-trioxo- (m, 3H),6.92 (t, J = 8.4 Hz, 1H), 3.73 (s, 3,4,6,7- 2H), 3.08 (s, 3H), 2.99 (s,3H), 2.82 (s, tetrahydropyrido[4,3- 3H), 2.63-2.55 (m, 1H), 1.21 (s,3H), d]pyrimidin-1(2H)- 0.96-0.94 (m, 2H), 0.67(brs, 2H).yl)phenyl)-N,N- MS: m/z 644.3 (M + 1). dimethylacetamide 30 vii2-(3-(3-cyclopropyl-5-((2- ¹HNMR (400 MHz, DMSO-d6), δ 11.08 fluoro-4-(s, 1H), 8.42 (brs, 1H), 8.07 (brs, 1H), iodophenyl)amino)-6,8- 7.79(dd, 1H, J = 1.6 & 10.4 Hz), 7.65- dimethyl-2,4,7-trioxo- 7.54 (m, 5H),6.94 (t, J = 8.4 Hz, 1H), 3.08 3,4,7,8- (s, 3H), 2.64-2.59 (m, 1H), 1.13(s, 3H), tetrahydropyrido[2,3- 0.98-0.93 (m, 2H), 0.70-0.66 (m, 2H).d]pyrimidin-1(2H)- MS: m/z 652.0 (M + 1). yl)phenyl)-2,2-difluoroacetamide 31 xvi 2-(3-(3-Cyclopropyl-5-((2- ¹HNMR (400 MHz,DMSO-d6), δ11.07 fluoro-4- (s, 1H), 8.85 (d, 1H, J = 6.4 Hz), 7.77 (d,iodophenyl)amino)-6,8- 1H, J = 9.6 Hz), 7.53 (d, 1H, J = 8.4 Hz),dimethyl-2,4,7-trioxo- 7.38 (t, 1H, J = 7.6 Hz), 7.27-7.16 (m, 3,4,6,7-3H), 6.91 (t, 1H, J = 8.8 Hz), 4.76-4.73 tetrahydropyrido[4,3- (m, 1H),4.71-4.67 (m, 2H), 4.39-4.36 d]pyrimidin-1(2H)- (m, 2H), 3.46 (s, 2H),3.08 (s, 3H), 2.55- yl)phenyl)-N-(oxetan-3- 2.54 (m, 1H), 1.16 (s, 3H),0.95-0.93 (m, yl)acetamide 2H), 0.7-0.6 (m, 2H). MS: m/z 672.0 (M + 1).32 xiii 2-(3-(3-Cyclopropyl-5-((2- ¹HNMR (400 MHz, DMSO-d6), δ 11.08fluoro-4- (s, 1H), 7.78 (d, 1H, J = 9.2 Hz), 7.54 (d,iodophenyl)amino)-6,8- 1H, J = 8.4 Hz), 7.46-7.36 (m, 4H), 7.30dimethyl-2,4,7-trioxo- (d, 1H, J = 7.6 Hz), 7.22 (s, 1H), 6.93-6.873,4,6,7- (m, 1H), 6.14 (d, 1H, J = 4.8 Hz), 4.88 (d,tetrahydropyrido[4,3- 1H, J = 4.8 Hz), 3.08 (s, 3H), 2.67-2.60d]pyrimidin-1(2H)- (m, 1H), 1.16 (s, 3H), 1.0-0.9 (m, 2H), yl)phenyl)-2-0.7-0.6 (m, 2H). hydroxyacetamide MS: m/z 632.0 (M + 1). 33 xvii3-Cyclopropyl-5-((2-fluoro- ¹HNMR (400 MHz, DMSO-d6), δ 11.114-iodophenyl)amino)-1-(3- (bs, 1H), 7.78 (dd, 1H, J = 1.6 and 10.4),(2-(3-hydroxyazetidin-1-yl)- 7.54 (d, 1H, J = 8.4), 7.40-7.36 (m, 1H),2-oxo ethyl)phenyl)-6,8- 7.27-7.23 (m, 2H), 7.20-7.14 (m, 1H),dimethylpyrido[4,3- 6.91 (t, 1H, J = 8.8 Hz), 5.72 (bs, 1H),d]pyrimidine- 4.42 (bs, 1H), 4.34-4.30 (m, 1H), 4.03-2,4,7(1H,3H,6H)-trione 3.99 (m, 1H), 3.89-3.59 (m, 1H), 3.58- 3.46 (m,1H), 3.33 (s, 2H), 3.07 (s, 3H), 2.63-2.60 (m, 1H), 1.19 (s, 3H), 0.95-0.93 (m, 2H), 0.65-0.64 (m, 2H). MS: m/z 672.0 (M + 1). 34 xxvi3-(3-(3-cyclopropyl-5-((2- ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 fluoro-4-(s, 1H), 7.78 (d, J = 10.4 Hz, 1H), 7.55 iodophenyl)amino)-6,8- (d , J =8.8 Hz, 1H), 7.37-7.30 (m, 2H), dimethyl-2,4,7-trioxo- 7.23-7.18 (m,3H), 6.92 (t, J = 8.4 Hz, 3,4,6,7- 1H), 6.75 (brs, 1H), 3.08 (s, 3H),2.82 (t, tetrahydropyrido[4,3- J = 7.6 Hz, 2H), 2.66-2.60 (m, 1H), 2.36d]pyrimidin-1(2H)- (t, J = 8.4 Hz, 2H), 1.16 (s, 3H), 0.96-yl)phenyl)propanamide 0.94 (m, 2H), 0.67-0.60 (m, 2H). MS: m/z 630.1(M + 1). 35 xxvii 2-(3-(3-cyclopropyl-5-((2- ¹H NMR (400 MHz, DMSO-d₆) δ11.05 fluoro-4- (s, 1H), 7.78 (dd, J = 10.0 and 1.6 Hz,iodophenyl)amino)-6,8- 1H), 7.58-7.53 (m, 2H), 7.42 (bs, 1H),dimethyl-2,4,7-trioxo- 7.37 (t, J = 8.0 Hz, 1H), 7.03-6.98 (m, 3,4,6,7-3H), 6.93 (t, J = 8.4 Hz, 1H), 4.43 (s, tetrahydropyrido[4,3- 2H), 3.07(s, 3H), 2.63-2.59 (m, 1H), d]pyrimidin-1(2H)- 1.25 (s, 3H), 0.96-0.94(m, 2H), 0.68- yl)phenoxy)acetamide 0.66 (m, 2H). MS: m/z 632.1 (M + 1).36 ix 3-(3-(3-cyclopropyl-5-((2- ¹H NMR (400 MHz, DMSO-d₆) δ 11.32fluoro-4- (s, 1H), 7.53 (dd, J = 9.6 and 2 Hz, 1H),iodophenyl)amino)-6,8- 7.46 (d, J = 8.4 Hz, 1H), 7.35 (t, J = 7.6dimethyl-2,4,7-trioxo- Hz, 1H), 7.23-7.20 (m, 1H), 7.15-7.12 3,4,6,7-(m, 2H), 6.71 (t, J = 8.0 Hz, 1H,), 5.4 tetrahydropyrido[4,3- (brs, 1H),3.2 1 (s, 3H), 3.00 (t, J = 7.2 d]pyrimidin-1(2H)- Hz, 2H), 2.76-2.72(m, 4H), 2.47 (t, J = yl)phenyl)-N- 7.2 Hz, 2H), 1.35 (s, 3H), 1.16-1.11(m, methylpropanamide 2H), 0.82-0.78 (m, 2H). MS: m/z 643.58 (M + 1). 37xxiv N-cyclopropyl-3-(3- ¹HNMR (400 MHz, DMSO-d6), δ 11.06cyclopropyl-5-((2-fluoro-4- (s, 1H), 8.53-8.52 (d, 1H, J = 4.4 Hz),iodophenyl)amino)-6,8- 7.85-7.82 (m, 1H), 7.80-7.77 (m, 2H),dimethyl-2,4,7-trioxo- 7.56-7.53 (m, 3H), 6.96-6.92 (t, 1H, 3,4,6,7- J =8 Hz), 3.08 (s, 3H), 2.86-2.82 (m, 1H), tetrahydropyrido[4,3- 2.64-2.59(m, 1H), 1.17 (s, 3H), 0.96- d]pyrimidin-1(2H)- 0.94 (m, 2H), 0.70-0.68(m, 4H), 0.60- yl)benzamide 0.56 (m, 2H). MS: m/z 642.0 (M + 1). 38 iv3-cyclopropyl-1-(3-(1,1- ¹HNMR (400 MHz, DMSO-d6), δ 11.03dioxidothiazolidine-3- (s, 1H), 7.78 (dd, 1H, J = 1.6 Hz and 10.4carbonyl)phenyl)-5-((2- Hz), 7.60-7.54 (m, 5H), 6.96-6.92 (t, 1H,fluoro-4- J = 8.8 Hz), 4.65 (bs, 2H), 4.01 (bs, 2H),iodophenyl)amino)-6,8- 3.48 (t, 2H J = 7.2 Hz), 3.07 (s, 3H), 2.66-dimethylpyrido[4,3- 2.55 (m, 1H), 1.17 (s, 3H), 0.98-0.90 (m,d]pyrimidine- 2H), 0.72-0.60 (m, 2H). 2,4,7(1H,3H,6H)-trione MS: m/z705.9 (M + 1). 39 v 3-cyclopropyl-1-(3-(1,1- ¹HNMR (400 MHz, CDCl3-d1),δ 11.29 dioxidothiomorpholine-4- (s, 1H), 7.55-7.53 (m, 2H), 7.49-7.47(m, carbonyl)phenyl)-5-((2- 3H), 7.39-7.37 (m, 1H), 6.73 (t, 1H,fluoro-4- J = 8.4 Hz), 4.18-4.14 (m, 4H), 3.23 (s,iodophenyl)amino)-6,8- 3H), 3.17-3.13 (m, 4H), 2.78-2.74 (m,dimethylpyrido[4,3- 1H), 1.39 (s, 3H), 1.16-1.14 (m, 2H), d]pyrimidine-0.85-0.75 (m, 2H). 2,4,7(1H,3H,6H)-trione MS: m/z 719.9 (M + 1). 40xviii N-cyclopropyl-3-(3-(3- ¹HNMR (400 MHz, DMSO-d6), δ 11.07cyclopropyl-5-((2-fluoro-4- (s, 1H), 7.94-7.77 (m, 1H), 7.91-7.90 (d,iodophenyl)amino)-6,8- 1H, J = 3.6 Hz), 7.55-7.53 (m, 1H), 7.36-dimethyl-2,4,7-trioxo- 7.32 (m, 1H), 7.22-7.17 (m, 3H), 6.89 (t,3,4,6,7- 1H J = 8 Hz), 3.07 (s, 3H), 2.83-2.79 (m, tetrahydropyrido[4,3-2H), 2.51 (bs, 2H), 2.31 (bs, 2H), 1.17 (s, d]pyrimidin-1(2H)- 3H),0.95-0.93 (m, 2H), 0.65 (bs, 2H), yl)phenyl)propanamide 0.58-0.53 (m,2H), 0.31-0.30 (bs, 2H). MS: m/z 670 (M + 1). 41 iiiN-cyclopropyl-2-(3-(5-((2- ¹HNMR (400 MHz, DMSO-d6), δ 11.19 fluoro-4-(s, 1H), 8.15 (d, J = 4.4 Hz, 1H), 7.79 iodophenyl)amino)-3,6,8- (dd, J= 2 and 10.4 Hz, 1H), 7.55 (dd, J = trimethyl-2,4,7-trioxo- 1.2 and 8.4Hz, 1H), 7.38 (t, J = 8.4 Hz, 3,4,6,7- 1H), 7.03-6.98 (m, 3H), 6.94 (t,J = 8.8 tetrahydropyrido[4,3- Hz, 1H), 4.45 (s, 2H), 3.21 (s, 3H), 2.69-d]pyrimidin-1(2H)- 2.64 (m, 1H), 2.08 (s, 3H), 1.26 (s, 3H),yl)phenoxy)acetamide 0.64-0.59 (m, 2H), 0.47-0.43 (m, 2H). MS: m/z 645.7(M + 1). 42 xxviii 2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ11.20 iodophenyl)amino)-3,6,8- (s, 1H), 7.79 (dd, J = 1.6 and 10.4 Hz,trimethyl-2,4,7-trioxo- 1H), 7.56-7.48 (m, 2H), 7.39 (t, J = 7.63,4,6,7- Hz, 1H), 7.30-7.24 (m, 3H), 6.95-6.90 tetrahydropyrido[4,3- (m,2H), 3.41 (s, 2H), 3.21 (s, 3H), 3.09 d]pyrimidin-1(2H)- (s, 3H), 1.20(s, 3H). yl)phenyl)acetamide MS: m/z 590.0 (M + 1). 43 vi2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ 11.25iodophenyl)amino)-3,6,8- (s, 1H), 7.79 (d, J = 10.4 Hz, 1H), 7.55 (d,trimethyl-2,4,7-trioxo- J = 8.0 Hz, 1H), 7.43-7.41 (m, 2H), 7.30-3,4,6,7- 7.27 (m, 2H), 6.98-6.90 (m, 3H), 3.22 (s, tetrahydropyrido[4,3-3H), 3.09 (s, 3H), 1.44 (s, 6H), 1.18 (s, d]pyrimidin-1(2H)- 3H)yl)phenyl)-2- MS: m/z 618.1 (M + 1). methylpropanamide 44 viii2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ 11.19iodophenyl)amino)-3,6,8- (s, 1H), 7.79 (dd, J = 1.6 & 10 Hz, 1H),trimethyl-2,4,7-trioxo- 7.55 (d, J = 8.4 Hz, 1H), 7.42-7.20 (m, 3,4,6,7-4H), 6.92 (t, J = 8.4 Hz, 1H), 3.73 (s, 2H), tetrahydropyrido[4,3- 3.21(s, 3H), 3.08 (s, 3H), 2.99 (s, 3H), d]pyrimidin-1(2H)- 2.82 (s, 3H),1.22 (s, 3H). yl)phenyl)-N,N- MS: m/z 618.1 (M + 1). dimethylacetamide45 vii 2,2-difluoro-2-(3-(5-((2- ¹HNMR (400 MHz, DMSO-d6), δ 11.20fluoro-4- (s, 1H), 8.41 (brs, 1H), 8.07 (brs, 1H),iodophenyl)amino)-3,6,8- 7.79 (dd, J = 1.2 & 10.0 Hz, 1H), 7.63-trimethyl-2,4,7-trioxo- 7.54 (m, 5H), 6.94 (t, J = 8.8 Hz, 1H), 3.093,4,6,7- (s, 3H), 3.21 (s, 3H), 1.14 (s, 3H). tetrahydropyrido[4,3- MS:m/z 626.0 (M + 1). d]pyrimidin-1(2H)- yl)phenyl)acetamide 46 xv1-(3-(2-(Azetidin-1-yl)-2- ¹HNMR (400 MHz, DMSO-d6), δ 11.20oxoethyl)phenyl)-5-((2- (s, 1H), 7.79 (dd, 1H, J = 10 & 1.6), 7.56-fluoro-4- 7.53 (m, 1H), 7.42-7.38 (m, 1H), 7.30-iodophenyl)amino)-3,6,8- 7.22 (m, 3H), 6.93 (t, 1H, J = 8.4 Hz),trimethylpyrido[4,3- 4.15 (t, 2H, J = 7.6 Hz), 3.83 (t, 2H, J =d]pyrimidine- 7.6 Hz), 3.43 (s, 2H), 3.21 (s, 3H), 3.08 (s,2,4,7(1H,3H,6H)-trione 3H), 2.18-2.15 (m, 2H), 1.2 (s, 3H). MS: m/z630.0 (M + 1). 47 xiii 2-(3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ11.21 iodophenyl)amino)-3,6,8- (s, 1H), 7.78 (dd, 1H, J = 1.6 & 8.8 Hz),trimethyl-2,4,7-trioxo- 7.54 (d, 1H, J = 8.8 Hz), 7.48-7.33 (m, 3,4,6,7-5H), 7.22 (s, 1H), 6.92 (t, 1H, J = 8.8 Hz), tetrahydropyrido[4,3- 6.15(bs, 1H), 4.88 (d, 1H, J = 4.8 Hz), d]pyrimidin- 3.21 (s, 3H), 3.08 (s,3H), 1.16 (s, 3H). 1(2H)-yl)phenyl)-2- MS: m/z 605 (M + 1).hydroxyacetamide 48 xvii 5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ11.20 iodophenyl)amino)-1-(3-(2- (s, 1H), 7.78 (d, 1H, J = 9.6 Hz), 7.54(d, (3-hydroxyazetidin-1-yl)-2- 1H, J = 8 Hz), 7.41-7.38 (m, 1H), 7.30-oxoethyl)phenyl)-3,6,8- 7.22 (m, 3H), 6.93 (t, 1H, J = 8.4 Hz),trimethylpyrido[4,3- 5.72 (d, 1H, J = 6), 4.42-4.35 (m, 1H),d]pyrimidine- 4.32-4.01 (m, 1H), 3.99-3.90 (m, 1H),2,4,7(1H,3H,6H)-trione 3.89-3.87 (m, 1H), 3.58-3.54 (m, 1H), 3.33 (s,2H), 3.20 (s, 3H), 3.08 (s, 3H), 1.2 (s, 3H). MS: m/z 646 (M + 1). 49 xi3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ 11.18iodophenyl)amino)-3,6,8- (s, 1H), 7.89-7.86 (m, 2H), 7.79 (dd, 1H,trimethyl-2,4,7-trioxo- J = 10.4 and 2 Hz), 7.59-7.54 (m, 3H), 3,4,6,7-6.95 (t, 1H, J = 8.4 Hz), 4.85 (t, 1H, J = tetrahydropyrido[4,3- 5.6Hz), 4.45-4.44 (m, 1H), 4.30-4.28 (m, d]pyrimidin-1(2H)-yl)-N- 2H),3.60-3.56 (m, 1H), 3.49-3.46 (m, (oxetan-3-yl)benzamide 1H), 3.19 (s,3H), 3.08 (s, 3H), 1.19 (s, 3H). MS: m/z 632.0 (M + 1). 50 xvi2-(3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ 11.20iodophenyl)amino)-3,6,8- (s, 1H), 8.85 (d, 1H, J = 6.4 Hz), 7.78 (d,trimethyl-2,4,7-trioxo- 1H, J = 10.4 Hz), 7.54 (d, 1H, J = 8.4 Hz),3,4,6,7- 7.41-7.37 (m, 1H), 7.30-7.24 (m, 3H), tetrahydropyrido[4,3-6.92 (t, 1H, J = 8.4 Hz), 4.78-4.74 (m, d]pyrimidin- 1H), 4.73-4.67 (m,2H), 4.38 (t, 2H, J = 6 1(2H)-yl)phenyl)-N- Hz), 3.46 (s, 2H), 3.20 (s,3H), 3.08 (s, (oxetan-3-yl)acetamide 3H), 1.18 (s, 3H). MS: m/z 646.0(M + 1). 51 xii 3-(5-((2-Fluoro-4- ¹HNMR (400 MHz, CDCl₃), δ 11.41 (s,iodophenyl)amino)-3,6,8- 1H), 7.79 (d, 1H, J = 7.6 Hz), 7.71 (bs,trimethyl-2,4,7-trioxo- 1H), 7.57-7.46 (m, 4H), 6.72 (t, 1H, J =3,4,6,7- 8.4 Hz), 6.46 (d, 1H, J = 7.6 Hz), 4.74 (bs,tetrahydropyrido[4,3- 1H), 4.12-3.82 (m, 4H), 3.39 (s, 3H), d]pyrimidin-3.23 (s, 3H), 2.41-2.35 (m, 1H), 2.00- 1(2H)-yl)-N- 1.90 (m, 1H), 1.35(s, 3H). (tetrahydrofuran-3- MS: m/z 646.0 (M + 1). yl)benzamide 52 xiv3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6) δ 11.21iodophenyl)amino)-3,6,8- (s, 1H), 8.42 (d, 1H, J = 7.6 Hz), 7.92-7.90trimethyl-2,4,7-trioxo- (m, 1H), 7.84 (s, 1H), 7.79 (dd, 1H, J = 23,4,6,7- & 8.4 Hz), 7.59-7.54 (m, 3H), 6.93 (t, tetrahydropyrido[4,3-1H, J = 8.8 Hz), 4.05-3.99 (m, 1H), 3.86 d]pyrimidin- (dd, 2H, J = 2 &9.2 Hz), 3.41-3.38 (m, 1(2H)-yl)-N-(tetrahydro- 2H), 3.21 (s, 3H), 3.08(s, 3H), 1.77-1.74 2H-pyran-4-yl)benzamide (m, 2H), 1.60-1.56 (m, 2H),1.19 (s, 3H). 53 xx 3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ: 11.2iodophenyl)amino)-3,6,8- (s, 1H), 8.79 (s, 1H), 7.91-7.78 (m, 3H),trimethyl-2,4,7-trioxo- 7.58-7.51 (m, 3H), 6.96 (t, 1H, J = 8.8 Hz),3,4,6,7- 4.79 (t, 1H, J = 6 Hz), 3.52 (bs, 2H), 3.21tetrahydropyrido[4,3- (s, 3H), 3.09 (s, 3H), 1.93 (s, 3H), 0.75-d]pyrimidin-1(2H)-yl)-N- 0.70 (m, 4H). (1-(hydroxymethyl)cyclo- MS: m/z646.0 (M + 1). propyl)benzamide 78 xxxi 1-(3-(3-cyclopropyl-5-((2- ¹HNMR(400 MHz, DMSO-d6), δ 11.05 fluoro-4-iodophenyl) (s, 1H), 7.79 (dd, J =1.6 and 8.8 Hz, 1H), amino)-6,8-dimethyl-2,4,7- 7.55 (dd, J = 1.2 and8.4 Hz, 1H), 7.45- trioxo-3,4,6,7- 7.29 (m, 4H), 7.19 (brs, 1H), 6.93(t, J = tetrahydropyrido[4,3- 8.4 Hz, 1H), 5.97 (brs, 1H), 3.08 (s, 3H),d] pyrimidin-1(2H)-yl) 2.62-2.59 (m, 1H), 1.35 (brs, 2H), 1.21phenyl)cyclopropanecarboxamide (s, 3H), 0.98-0.93 (m, 4H), 0.69-0.65 (m,2H). MS: m/z 642.0 (m + 1)

Example-5:N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide(Compound 54)

To a mixture ofN-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide(2) (110 mg, 0.183 mmol) and K₂CO₃ (0.51 mg, 0.37 mmol) in DMF (3 ml)was added Iodomethane (9.15 μl, 0.146 mmol) portion wise. The solutionwas heated at 60° C. for 3 hrs. The reaction mixture was cooled to roomtemperature followed by the addition of water and the mixture wasextracted with ethyl acetate (3×10 ml). The combined organic layers werewashed with water, brine and dried over sodium sulfate. The organiclayer was concentrated to obtain a crude product, which was purified bycolumn chromatography to yield the product (55) (0.06 gm).

¹H NMR (400 MHz, DMSO-d₆) δ 11.19 (s, 1H), 8.53 (d, 1H, J=4 Hz),7.87-7.84 (m, 1H), 7.80-7.77 (m, 2H), 7.59-7.54 (m, 3H), 6.95 (t, 1H,J=8.0 Hz), 3.21 (s, 3H), 3.09 (s, 3H), 2.85-2.83 (m, 1H), 1.18 (s, 3H),0.70-0.68 (m, 2H), 0.58-0.57 (m, 2H).

MS: m/z 616.1 (M+1)].

The compounds given below in Table 4: were prepared by procedure similarto the one described above in Example 5 using the above preparedcompounds as starting material and with appropriate variations inreactants, reaction conditions and quantities of reagents.

TABLE 4 Cmpd. Intermed. No. Name Analytical data 55 2N-cyclopropyl-3-(5-((2- ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 fluoro-4- (s,1H), 8.56 (d, 1H, J = 4 Hz), 7.87-7.78 iodophenyl)amino)-3-(2- (m, 3H),7.58-7.52 (m, 3H), 6.96 (t, 1H, hydroxyethyl)-6,8- J = 8.4 Hz), 4.80 (t,1H, J = 6 Hz), 3.93 (t, dimethyl-2,4,7-trioxo- 2H, J = 6.4), 3.55-3.51(m, 2H), 3.08 (s, 3,4,6,7- 3H), 2.86-2.81 (m, 1H), 1.17 (s, 3H),tetrahydropyrido[4,3- 0.70-0.68 (m, 2H), 0.58-0.57 (m, 2H),d]pyrimidin-1(2H)- MS: m/z 646.1 (M + 1)]. yl)benzamide 56 31-(3-(azetidine-1- ¹H NMR (400 MHz, CDCl3) δ 11.39 (s,carbonyl)phenyl)-5-((2- 1H), 7.66-7.62 (m, 2H), 7.55-7.51 (m, fluoro-4-2H), 7.50-7.43 (m, 2H), 6.71 (t, 1H, iodophenyl)amino)-3,6,8- J = 8 Hz),4.4-4.28 (m, 4H), 3.38 (s, 3H), trimethyl pyrido[4,3- 3.23 (s, 3H),2.41-2.33 (m, 2H), 1.34 (s, d]pyrimidine- 3H). 2,4,7(1H,3H,6H)-trioneMS: m/z 616.1 (M + 1)]. 57 16 2-(3-(5-((2-fluoro-4- ¹H NMR (400 MHz,DMSO-d₆) δ 11.19 iodophenyl)amino)-3,6,8- (s, 1H), 7.78 (d, 1H, J = 8Hz), 7.57-7.53 trimethyl-2,4,7-trioxo- (m, 2H), 7.41-7.35 (m, 2H),7.04-7.00 3,4,6,7- (m, 3H ), 6.93 (t, 1H, J = 8 Hz ), 4.43 (s,tetrahydropyrido[4,3- 2H), 3.20 (s, 3H), 3.08 (s, 3H), 1.27 (s,d]pyrimidin-1(2H)- 3H). yl)phenoxy)acetamide MS: m/z 605.9 (M + 1)]. 584 N-cyclopropyl-2-(3-(5-((2- ¹H NMR (400 MHz, DMSO-d₆) δ 11.20 fluoro-4-(s, 1H), 8.14 (d, 1H, J = 4 Hz), 7.79 (dd, iodophenyl)amino)-3,6,8- 1H,J = 2 and 10.4 Hz), 7.55 (dd, 1H, J = trimethyl-2,4,7-trioxo- 1.2 and8.4 Hz), 7.41-7.37 (m, 1H), 7.30- 3,4,6,7- 7.22 (m, 3H), 6.93 (t, 1H, J= 8.8 Hz), 3.37 tetrahydropyrido[4,3- (s, 2H), 3.21 (s, 3H), 3.08 (s,3H), 2.59- d]pyrimidin-1(2H)- 2.56 (m, 1H), 1.18 (s, 3H), 0.60-0.58 (m,yl)phenyl)acetamide 2H), 0.37-0.33 (m, 2H). MS: m/z 630.1 (M + 1)]. 59 4N-cyclopropyl-2-(3-(3 - ¹H NMR (400 MHz, DMSO-d₆) δ 11.23ethyl-5-((2-fluoro-4- (s, 1H), 8.14 (d, 1H, J = 4 Hz), 7.79 (dd,iodophenyl)amino)-6,8- 1H, J = 1.6 and 10.4 Hz), 7.55 (d, 1H, J =dimethyl-2,4,7-trioxo- 8.4 Hz), 7.41-7.37 (m, 1H), 7.31-7.23 (m,3,4,6,7- 3H), 6.94 (t, 1H, J = 8.8 Hz), 3.87 (q, 2H,tetrahydropyrido[4,3- J = 7.2 Hz), 3.37 (s, 2H), 3.08 (s, 3H),d]pyrimidin-1(2H)- 2.59-2.55 (m, 1H), 1.18 (s, 3H), 1.11 (t,yl)phenyl)acetamide 3H, J = 9 Hz), 0.60-0.58 (m, 2H), 0.35- 0.33 (m,2H). MS: m/z 643.9 (M + 1)]. 60 5 2-(3-(5-((2-fluoro-4- ¹H NMR (400 MHz,DMSO-d₆) δ 11.18 iodophenyl)amino)-3,6,8- (s, 1H), 8.07-8.06 (d, 1H, J =4 Hz), 7.79 trimethyl-2,4,7-trioxo- (dd, 1H, J = 2 and 10.4 Hz),7.56-7.54 3,4,6,7- (m, 1H), 7.40-7.36 (m, 1H), 7.04-7.01tetrahydropyrido[4,3- (m, 3H), 6.93 (t, 1H, J = 8 Hz), 4.47 (s,d]pyrimidin-1(2H)- 2H), 3.20 (s, 3H), 3.08 (s, 3H), 2.64 (d,yl)phenoxy)-N- 3H, J = 4 Hz), 1.23 (s, 3H). methylacetamide MS: m/z616.1 (M + 1)]. 61 1 3-(3-(3-ethyl-5-((2-fluoro- ¹HNMR (400 MHz,DMSO-d6), δ 11.25 4-iodophenyl)amino)-6,8- (s, 1H), 7.79 (dd, J = 2 and10.4 Hz, 1H), dimethyl-2,4,7-trioxo- 7.55 (d, J = 8.4 Hz, 1H), 7.43-7.32(m, 3,4,6,7- 2H), 7.27-7.22 (m, 3H), 6.95 (t, J = 8.4tetrahydropyrido[4,3- Hz, 1H). 6.79 (s, 1H), 3.87 (q, J = 7.2 Hz,d]pyrimidin-1(2H)- 2H), 3.08 (s, 3H), 2.82 (t, J = 7.6 Hz,yl)phenyl)propanamide 2H), 2.38-2.35 (m, 2H), 1.19 (s, 3H), 1.13 (t, J =7.2 Hz, 3H). MS: m/z 618.1 (M + 1)]. 62 2 N-cyclopropyl-3-(3-ethyl-¹HNMR (400 MHz, DMSO-d6), δ 11.24 5-((2-fluoro-4- (s, 1H), 8.54 (d, J =4.4 Hz, 1H), 7.87- iodophenyl)amino)-6,8- 7.78 (m, 3H), 7.61-7.52 (m,3H), 6.97 (t, dimethyl-2,4,7-trioxo- J = 8.8 Hz, 1H), 3.87 (q, J = 7.2Hz, 2H), 3,4,6,7- 3.08 (s, 3H), 2.86-2.81 (m, 1H), 1.17-tetrahydropyrido[4,3- 1.08 (m, 6H), 0.70-0.68 (m, 2H), 0.58-d]pyrimidin-1(2H)- 0.57 (m, 2H). yl)benzamide MS: m/z 630.1 (M + 1)]. 637 5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ iodophenyl)amino)-3,6,8-11.17(s, 1H), 7.79 (d, J-10.4 Hz, 1H), trimethyl-1-(3- 7.57-7.44 (m,5H), 6.95 (t, J = 8.8 Hz, (morpholine-4- 1H), 3.62-3.36 (m, 8H), 3.21(s, 3H), 3.09 carbonyl)phenyl) (s, 3H), 1.21 (s, 3H).pyrido[4,3-d]pyrimidine- MS: m/z 645.9 (M + 1)]. 2,4,7(1H,3H,6H)-trione64 2 ethyl 2-(1-(3- ¹HNMR (400 MHz, DMSO-d6), δ 10.96(cyclopropylcarbamoyl)phenyl)- (s, 1H), 8.58 (d, J = 4.0 Hz, 1H),7.89-7.78 5-((2-fluoro-4- (m, 3H), 7.60-7.54 (m, 3H), 7.03 (t, J = 8.4iodophenyl)amino)-6,8- Hz, 1H), 4.60 (s, 2H), 4.12 (q, J = 6.8 Hz,dimethyl-2,4,7-trioxo- 2H), 3.08 (s, 3H), 2.87-2.82 (m, 1H), 1,2,6,7-1.24 (s, 3H), 1.19 (t, J = 4.8 Hz, 3H), 0.88- tetrahydropyrido[4,3- 0.84(m, 2H), 0.70 (m, 2H) d]pyrimidin-3(4H)- yl)acetate 65 8 1-(3-(1,1-¹HNMR (400 MHz, DMSO-d6), δ dioxidothiomorpholine-4- 11.17(s, 1H), 7.79(dd, J = 2 & 10.4 Hz, carbonyl)phenyl)-5-((2- 1H), 7.59-7.50 (m, 5H),6.95 (t, J = 8.8 fluoro-4- Hz, 1H), 4.00-3.69 (m, 4H), 3.38-3.26iodophenyl)amino)-3,6,8- (m, 4H), 3.22(s, 3H), 3.08 (s, 3H), 1.22trimethylpyrido[4,3- (s, 3H). d]pyrimidine- MS: m/z 694.0 (M + 1)]2,4,7(1H,3H,6H)-trione 66 8 1-(3-(1,1- ¹HNMR (400 MHz, DMSO-d6), δ 11.20dioxidothiomorpholine-4- (s, 1H), 7.79 (dd, J = 1.6 & 10.4 Hz, 1H),carbonyl)phenyl)-3-ethyl- 7.61-7.51 (m, 5H), 6.97 (t, J = 8.4 Hz,5-((2-fluoro-4- 1H), 4.04-4.00 (m, 2H), 3.88 (q, J = 6.4iodophenyl)amino)-6,8- Hz, 2H), 3.69 (m, 2H), 3.28-3.27 (m,dimethylpyrido[4,3- 4H), 3.08 (s, 3H), 1.21 (s, 3H), 1.16 (t,d]pyrimidine- J = 6.4 Hz, 3H). 2,4,7(1H,3H,6H)-trione MS: m/z 708.0 (M +1)]. 67 10 2-(3-(3-ethyl-5-((2-fluoro- ¹HNMR (400 MHz, DMSO-d6), δ 11.234-iodophenyl)amino)-6,8- (s, 1H), 7.79 (dd, J = 1.6 & 10 Hz, 1H),dimethyl-2,4,7-trioxo- 7.54 (d, J = 8.4 Hz, 1H), 7.42-7.22 (m, 3,4,6,7-4H), 6.95 (t, J = 8.8 Hz, 1H), 3.87 (q, tetrahydropyrido[4,3- J = 6.8Hz, 2H), 3.73 (s, 2H), 3.08 (s, 3H), d]pyrimidin-1(2H)- 2.99 (s, 3H),2.82 (s, 3H), 1.21 (s, 3H), yl)phenyl)-N,N- 1.11 (t, J = 7.2 Hz, 3H).dimethylacetamide MS: m/z 632.5 (M + 1)]. 68 1 3-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d₆) δ 11.20 iodophenyl)amino)-3,6,8- (s, 1H), 7.79(dd, J = 10.4 and 1.6 Hz, trimethyl-2,4,7-trioxo- 1H), 7.54 (d, J = 8.4Hz, 1H), 7.37 (t, J = 3,4,6,7- 8.4 Hz, 1H), 7.31 (brs, 1H), 7.27-7.21(m, tetrahydropyrido[4,3- 3H), 6.93 (t, J = 8.4 Hz, 1H), 6.77 (brs,d]pyrimidin-1(2H)- 1H), 3.20 (s, 3H), 3.08 (s, 3H), 2.82 (t, J =yl)phenyl)propanamide 7.6 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H), 1.19 (s,3H). MS: m/z 604.1 (M + 1)]. 69 2 N-cyclopropyl-3-(5-((2- ¹HNMR (400MHz, DMSO-d6), δ 11.21 fluoro-4- (s, 1H), 8.54-8.53 (d, 1H, J = 4 Hz),7.86- iodophenyl)amino)-3- 7.77 (m, 3H), 7.59-7.52 (m, 3H), 6.99-isopropyl-6,8-dimethyl- 6.95 (t, 1H, J = 8.8 Hz), 4.97-4.94 (m,2,4,7-trioxo-3,4,6,7- 1H), 3.07 (s, 3H), 2.86-2.81 (m, 1H),tetrahydropyrido[4,3- 1.39-1.37 (m, 6H), 1.16 (s, 3H), 0.70-d]pyrimidin-1(2H)- 0.68 (m, 2H), 0.59-0.56 (m, 2H). yl)benzamide MS: m/z644.1 (M + 1)]. 70 2 3-(3-allyl-5-((2-fluoro-4- ¹HNMR (400 MHz,DMSO-d6), δ 11.16 iodophenyl)amino)-6,8- (s, 1H), 8.54 (d, 1H, J = 4Hz), 7.87-7.84 dimethyl-2,4,7-trioxo- (m, 1H), 7.87-7.78 (m, 3H),7.59-7.53 3,4,6,7- (m, 3H), 6.98 (t, 1H, J = 8.4 Hz), 5.85-5.80tetrahydropyrido[4,3- (m, 1H), 5.19-5.10 (m, 1H ), 4.44 (d, 2H,d]pyrimidin-1(2H)-yl)-N- J = 5.6 Hz), 3.08 (s, 3H), 2.85-2.81 (m,cyclopropylbenzamide 1H), 1.18 (s, 3H), 0.70-0.68 (m, 2H), 0.58-0.57 (m,2H). MS: m/z 641.4 (M + 1)]. 71 16 2-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz,DMSO-d6), δ 11.05 iodophenyl)amino)-6,8- (s, 1H), 7.56-7.49 (m, 2H),7.41 (t, 1H, dimethyl-3-(oxetan-3-yl)- J = 8.0 Hz), 6.97-6.89 (m, 3H),6.75 (t, 1H, 2,4,7-trioxo-3,4,6,7- J = 8.0 Hz), 6.51 (s, 1H), 5.72 (s,1H), 5.03- tetrahydropyrido[4,3- 5.01 (m, 1H), 4.90-4.82 (m, 2H), 4.52(s, d]pyrimidin-1(2H)- 2H), 4.14-4.08 (m, 2H), 3.21 (s, 3H),yl)phenoxy)acetamide 1.44 (s, 3H). MS: m/z 648.0 (M + 1)]. 79 771-(3-(5-((2-fluoro-4- ¹HNMR (400 MHz, DMSO-d6), δ 11.19iodophenyl)amino)-3,6,8- (s, 1H), 7.79 (dd, J = 2 and 10.4 Hz, 1H),trimethyl-2,4,7-trioxo- 7.55 (dd, J = 1.2 and 8.4 Hz, 1H), 7.46-3,4,6,7- 7.32 (m, 4H), 7.33 (brs, 1H), 6.94 (t, J =tetrahydropyrido[4,3- 8.8 Hz, 1H), 6.09 (s, 1H), 3.21 (s, 3H),d]pyrimidin-1(2H)- 3.09 (S, 3H), 1.35 (brs, 2H), 1.23 (s, 3H),yl)phenyl)cyclopropanecarboxamide 0.98 (brs 2H). MS: m/z 616.0 (m + 1)

Example 6:N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 72)

5 ml DMF was added toN-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide(Compound 2) (200 mg, 0.333 mmol), to the mixture Potassium Carbonate(230 mg, 1.663 mmol) was added and the mixture was stirred at 60° C. for20 min period and Sodium chlorodifluoroacetatae (101 mg, 0.665 mmol) wasadded and the mixture was heated at 90° C. for 18 hrs. The reactionmixture was cooled to room temperature followed by the addition of waterand the mixture was extracted with ethyl acetate (3×10 ml). The combinedorganic layers were washed with water, brine and dried over sodiumsulfate. The organic layer was concentrated to obtain a crude product,which was purified by column chromatography to yield the product (72) assolid (0.05 mg).

¹HNMR (400 MHz, DMSO-d6), δ 10.53 (s, 1H), 8.56-8.55 (d, 1H, J=4 Hz),7.87-7.84 (m, 2H), 7.80-7.78 (m, 1H), 7.65-7.51 (m, 4H), 7.07-7.03 (t,1H J=8 Hz), 3.09 (s, 3H), 2.85-2.82 (m, 1H), 1.19 (s, 3H), 0.70-0.68 (m,2H), 0.59-0.58 (m, 2H).

MS: m/z 651.9 (M+1)].

Example 7:N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide(Compound 73)

To a stirred solution of3-(3-allyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-cyclopropylbenzamide(compound 70) (180 mg, 0.281 mmol) and 4-methylmorpholine N-oxide (32.9mg, 0.281 mmol) in THF (3 ml) was added osmium tetraoxide (10% in water)(0.088 ml, 0.281 mmol) slowly. Reaction was stirred at room temperaturefor 3 hrs. Water (20 mL) was added to the reaction mixture and themixture was extracted with ethyl acetate (3×10 ml). The combined organiclayers were washed with water, brine and dried over sodium sulfate. Theorganic layer was concentrated under vacuum to obtain a crude product,which was purified by column chromatography using a gradient ofhexane-90% ethyl acetate in hexane eluent to yield the product (73) (100mg).

¹H NMR (400 MHz, DMSO-d₆) δ 11.29 (s, 1H), 8.56 (d, 1H, J=4 Hz),7.87-7.84 (m, 1H), 7.83-7.78 (m, 2H), 7.57-7.52 (m, 3H), 6.96 (t, 1H,J=8.8 Hz), 4.79 (d, 1H, J=5.6), 4.59 (t, 1H, J=5.6 Hz), 4.01-3.98 (m,1H), 3.82-3.76 (m, 2H), 3.40-3.30 (m, 2H), 3.08 (s, 3H), 2.86-2.81 (m,1H), 1.18 (s, 3H), 0.70-0.68 (m, 2H), 0.58-0.57 (m, 2H).

MS: m/z 676.1 (M+1)].

Example 8:2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)aceticacid (Compound 74)

To a solution of ethyl2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetate(compound 64) (66 mg, 0.096 mmol) in THF:Water (2 ml, 7:3) was addedlithium hydroxide (8.06 mg, 0.192 mmol). The reaction mixture wasstirred at room temperature for 3 h. Reaction mixture was concentratedunder vacuum and treated with 2N HCl, the precipitate were collected byfiltration and purified by flash chromatography to give the pure product(74) (28 mg).

¹HNMR (400 MHz, DMSO-d6), δ 13.09 (bs, 1H), 11.03 (s, 1H), 8.57 (d, J=4Hz, 1H), 7.83 (m, 3H), 7.61-7.54 (m, 3H), 7.03 (t, J=8.8 Hz, 1H), 4.51(s, 2H), 3.08 (s, 3H), 2.86-2.83 (m, 1H), 1.19 (s, 3H), 0.70-0.68 (m,2H), 0.58-0.50 (m, 2H).

MS: m/z 659.9 (M+1)].

Example 9 Enantiomeric separation of2-(3-(5-((2-Fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxy acetamide (compound47)

Compound 47 was enantiomerically separated by using the preparative HPLCby the methods described below.

Method-1

Column: CHIRAL PAK IA, 250 mm×4.6μ. Flow 1.5 ml/min, Mobile Phase:A=hexane: IPA (90:10% v/v, 0.1% DEA), B=MeOH:EtOH (1:1). A:B=60:40 v/v

Method-2

Column: CHIRAL IA, 250 mm×4.6μ. Flow 1.5 ml/min, Mobile Phase:A=n-hexane: IPA (90:10% v/v, 0.1% DEA), B=MeOH:EtOH (1:1). A:B=85:15 v/v

(R)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide(Compound 75)

¹HNMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 7.78 (dd, 1H, J=2 and 8.4 Hz),7.55 (d, 1H, J=8.4 Hz), 7.48-7.33 (m, 5H), 7.22 (s, 1H), 6.93 (t, 1H,J=8.4 Hz), 6.15 (bs, 1H), 4.88 (d, 1H, J=4.8 Hz), 3.21 (s, 3H), 3.08 (s,3H), 1.17 (s, 3H). MS: m/z 606.1 (M+1)].

Retention time is 6.56.

(S)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide(Compound 76)

¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 7.78 (dd, 1H, J=2 and 8.4Hz), 7.55 (dd, 1H, J=1.2 and 7.2 Hz), 7.48-7.33 (m, 5H), 7.22 (s, 1H),6.93 (t, 1H, J=8.4 Hz), 6.15 (bs, 1H), 4.88 (d, 1H, J=4.8 Hz), 3.21 (s,3H), 3.08 (s, 3H), 1.17 (s, 3H).

MS: m/z 606.1 (M+1)].

Retention time is 8.93.

Pharmacological Activity:

In-Vitro Experiments:

Example-A: Identification of Compounds Inhibiting MEK Kinase Activity

In a 25 μL reaction, MEK enzyme (final concentration 2-4 μg/ml), and ERKsubstrate (final concentration 50-100 μg/ml), were incubated withvarious concentration of test compounds (diluted such that the reactionhad 1% DMSO), at 25-30° C. for 20 to 120 min on a shaker incubator. Thereactions were initiated by the addition of ATP. The reactions wereterminated by adding an equal volume of KinaseGlo reagent (Promega),following the manufacturer's instructions. The plates were read on aluminometer. IC₅₀ calculations were done using GraphPad Prism 5.

IC₅₀ values of the compounds of inventions were provided below in table5. Compounds exhibiting IC₅₀ in the range 1 nM to 499 nM were grouped as‘a’, compounds exhibiting IC₅₀ value in the range 0.5 μM to 1.5 μM weregrouped as ‘b’, and the compounds exhibiting IC₅₀ value in the range 1.6μM to 3.0 μM were grouped as ‘c’.

TABLE 5 MEK kinase inhibition activity of the compounds (IC₅₀): GroupCompound No. a 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 37, 38,39, 40, 41, 43, 44, 46, 48, 50, 54, 57, 58, 60, 61, 62, 63, 65, 66, 67,68, 73, 76, 77, 78, 79 b 3, 25, 36, 42, 45, 47, 49, 51, 52, 55, 56, 59,75. c 22, 53, 69, 71, 72, 74.

Example-B: Analysis of ERK Phosphorylation

This assay was carried out with human melanoma cells, human and mousecolon cancer cells. Cells were treated for 1 h with variousconcentrations of test compounds. ERK phosphorylation analysis wasperformed using the Alphascreen SureFire Phospho-ERK 1/2 Kit (PerkinElmer), by following the manufacturer's instructions. % inhibition ofERK phosphorylation was determined as:

100−{(RFU test−RFU lysis buffer control)/(RFU vehicle treatedcontrol−RFU lysis buffer control)}×100. The compounds prepared weretested using the above assay procedure and the results obtained aregiven in Table 6. Percentage inhibition at concentrations of 0.01 nM,0.03 nM, 0.1-0.9 nM, 1 nM to 3 nM, 4-100 nM, and >100 nM, for the statedexamples is setworth here. The percentage inhibiton at the abovedepicted concentrations for the compounds stated are given in thefollowing groups.

TABLE 6 Minimum concentration (nM) required for ≥80% inhibition of pERKCompound No 0.01 2, 6, 13, 31, 46, 49, 51, 66 0.03 35 0.1-0.9 5, 9, 10,11, 17, 21, 24, 25, 28, 29, 38, 41, 42, 43, 44, 47, 60, 65, 67, 78, 771-3 1, 3, 4, 8, 15, 16, 20, 27, 30, 32, 33, 34, 36, 37, 39, 45, 48, 54,56, 57, 58, 59, 61, 63, 68, 75  4-100 7, 12, 14, 18, 19, 22, 23, 26, 40,50, 52, 53, 55, 62, 71, 72, 73, 76, 79 >100 69, 74

Example-C: Analysis of B-Raf-Mediated MEK Phosphorylation

This assay was carried out with human melanoma cells. Cells were treatedfor 1 h with various concentrations of test compounds. MEKphosphorylation (S218 and S222) analysis was performed using theAlphascreen SureFire Phospho-MEK Kit (Perkin Elmer), by following themanufacturer's instructions. % inhibition of ERK phosphorylation wasdetermined as:

100−{(RFU test−RFU lysis buffer control)/(RFU vehicle treatedcontrol−RFU lysis buffer control)}×100. The % inhibition of MEKphosphorylation at concentrations of 100 nM, 10 nM and 1 nM for some ofthe compounds of the present invention is showed in table-7.

TABLE 7 % Inhibition of MEK Compound No. Concentration (nM)phosphorylation Compound 2 100 96.4 10 93.4 1 72.2 Compound 5 100 97.410 97.4 1 93.9 Compound 16 100 94.71 10 93.33 1 89.24 Compound 29 10076.4 10 72.9 1 52.9 Compound 37 100 92.39 10 85.92 1 54.69 Compound 57100 83.01 10 76.44 1 63.31 Compound 77 100 85.5 10 67.8 1 49.0 Compound78 100 75.4 10 56.7 1 42.6

In-Vivo Experiments

Athymic nude mice were acclimatized in the experimental animal room for15 days prior to the cell inoculation. Mice were inoculatedsubcutaneously at 5×10⁶ COLO205/A375 cells (in 0.2 mL PBS) single cellsuspension without conglomerates with viability of 98% into the rightflank of the mice. Post cell inoculation, tumor dimension were measuredwith digimatic Vernier caliper (Mitutoyo, Japan) when tumor becomespalpable. Tumor volume was calculated by using the formula:Tumor Volume in Mm³(Length×Width×Width)/2

Mice were randomized on the basis of tumor volume into different groupswith approximately equal mean and equal variation on desired day postcell inoculation. All groups were orally administered once/twice dailywith some compounds of the invention and vehicle control for 21/22 days.Tumor measurements were done with Vernier caliper twice weekly. Bodyweights of mice were recorded daily.

Percentage change in body weight was calculated as per the followingformula:(Final body weight−Initial body weight)/(Initial body weight)×100

Percent tumor growth inhibition was calculated as:

$= {I - {\left( \frac{\left( {{Tf} - {Ti}} \right)}{\left( {{Cf} - {Ci}} \right)} \right) \times 100}}$

Where, Tf and Ti, are the final and initial treatment tumor volumes, andCf and Ci are the final and initial control mean tumor volumes,respectively.

Percent tumor regression (TR %) was calculated as:

$= {\left( \frac{\left( {{{Final}\mspace{14mu}{day}\mspace{14mu}{tumor}\mspace{14mu}{volume}} - {{Initial}\mspace{14mu}{day}{\mspace{11mu}\;}{tumor}\mspace{14mu}{volume}}} \right)}{\left( {{Initial}{\mspace{11mu}\;}{day}\mspace{14mu}{tumor}\mspace{14mu}{volume}} \right)} \right) \times 100}$

Data was analyzed by GraphPad Prism 5.00 software using Two-way ANOVAfollowed by Bonferroni post hoc test. Differences were consideredsignificant at *p<0.05, **p<0.01 and ***p<0.001 treatment versus vehiclecontrol group.

The compounds 2, 5, 9, and 35 were tested for tumor growth in Colo205xenograft nude mice model using the assay procedure given above; the %of tumour growth inhibition after 20 days at 1 mg/kg dose was found tobe in the range 60% to 100%.

The foregoing description is considered illustrative only of theprinciples of the disclosure. Further, since numerous modifications andchanges will readily be apparent to those skilled in the art, it is notintended to limit the disclosure to the exact construction and processshown as described herein. Accordingly, all suitable modifications andequivalents may be resorted to as falling within the scope of thedisclosure and as defined by the claims that follow.

The words “comprise”, “comprising”, “include” and “including” when usedin this specification and in the following claims are intended tospecify the presence of the stated features, integers, components, orsteps, but they do not preclude the presence or addition of one or moreadditional features, integers, components, or steps thereof.

The invention claimed is:
 1. A method for treatment of lung cancer in anindividual in need thereof comprising administering to said individualan effective amount of a composition comprising a compound of formula(I), its tautomeric forms, its stereoisomers, or its pharmaceuticallyacceptable salts,

wherein: R¹ is selected from the group consisting of hydrogen,substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-alkynyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-cycloalkenyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl; R² is selected from the group consisting of—(C(R^(c))(R^(d)))_(m)—C(═O)—N(R⁶)R⁷, —C(═O)N(R⁸)R⁹ and—O—(C(R^(c))(R^(d)))_(m)—C(═O)—N(R⁶)R⁷; R³ is selected from the groupconsisting of hydrogen, substituted- or unsubstituted-alkyl, andsubstituted- or unsubstituted-cycloalkyl; R⁴ is selected from the groupconsisting of hydrogen, halogen, substituted- or unsubstituted-alkyl,and substituted- or unsubstituted-cycloalkyl; R⁵ is substituted- orunsubstituted-aryl, wherein the substituents are selected from R^(a) andR^(b); R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, substituted- or unsubstituted-alkyl,substituted- or unsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl; or R⁶ and R⁷ taken together with thenitrogen to which they are attached form a substituted- orunsubstituted-heterocycle; R⁸ and R⁹ are each independently selectedfrom the group consisting of hydrogen, substituted- orunsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl, or R⁸ and R⁹ taken together with thenitrogen to which they are attached form a substituted- orunsubstituted-heterocycle; with the provisos that both R⁸ and R⁹ cannotbe hydrogen at the same time; and when R⁸ and R⁹ are not a part of aheterocycle formed together with the nitrogen to which they areattached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl;R^(a) and R^(b) are selected from the group consisting of hydrogen,halogen, and haloalkyl; R^(c) and R^(d) are independently selected fromthe group consisting of hydrogen, halogen, hydroxyl, and substituted- orunsubstituted-alkyl; or R^(c) and R^(d) taken together with the carbonto which they are attached form a substituted- orunsubstituted-cycloalkyl; m is an integer selected from the groupconsisting of 1, 2, 3, and 4; further wherein: when the alkyl group oralkenyl group is substituted, the alkyl group or alkenyl group issubstituted with 1 to 4 substituents independently selected from thegroup consisting of oxo, halogen, nitro, cyano, perhaloalkyl,cycloalkyl, aryl, heteroaryl, heterocyclyl, —OR^(10b), —SO₂R^(10a),—C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰, —OR^(10a),—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰,—N(alkyl)R¹⁰—N(H)C(═O)N(H)R¹⁰, —N(H)C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl, and—NH—SO₂-cycloalkyl; when the cycloalkyl group or cycloalkenyl group issubstituted, the cycloalkyl group or cycloalkenyl group is substitutedwith 1 to 3 substituents independently selected from the groupconsisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl,hydroxyalkyl, aryl, heteroaryl, heterocyclyl, —OR^(10b), —SO₂R^(10a),—C(═O)R^(10a), —C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰,—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰, —N(alkyl)R¹⁰,—N(H)C(═O)N(H)R¹⁰, and —N(H)C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl, and—NH—SO₂-cycloalkyl; when the aryl group is substituted, the aryl groupis substituted with 1 to 3 substituents independently selected from thegroup consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl,—O-perhaloalkyl, —N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl,—SO₂-perhaloalkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl,—C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl,—SO₂N(H)alkyl, —SO₂NH₂, —NH—SO₂-alkyl, and —NH—SO₂-cycloalkyl; when theheteroaryl group is substituted, the heteroaryl group is substitutedwith 1 to 3 substituents independently selected from the groupconsisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, —O-alkyl,O-perhaloalkyl, —N(alkyl)alkyl, —N(H)alkyl, —NH₂, —SO₂-alkyl,—SO₂-perhaloalkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl,—C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH₂, —SO₂N(alkyl)alkyl,—SO₂N(H)alkyl, —SO₂NH₂, —NH—SO₂-alkyl, and —NH—SO₂-cycloalkyl; when theheterocyclyl group is substituted, the heterocyclyl group is substitutedwith 1 to 3 substituents, when the heterocyclic group is substituted ona ring carbon of the ‘heterocycle’, the substituents are independentlyselected from the group consisting of halogen, nitro, cyano, oxo, alkyl,alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocyclyl, —OR^(10b), —C(═O)OR^(10a), —OC(═O)R^(10a), —C(═O)N(H)R¹⁰,—C(═O)N(alkyl)R¹⁰, —N(H)C(═O)R^(10a), —N(H)R¹⁰, —N(alkyl)R¹⁰,—N(H)C(═O)N(H)R¹⁰, —N(H)C(═O)N(alkyl)R¹⁰; when the heterocyclic group issubstituted on a ring nitrogen of the ‘heterocycle’, the substituentsare independently selected from the group consisting of alkyl, alkenyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl, —SO₂R^(10a), —C(═O)R^(10a),C(═O)OR^(10a), —C(═O)N(H)R¹⁰, —C(═O)N(alkyl)R¹⁰, —NH—SO₂-alkyl and—NH—SO₂-cycloalkyl; when the heterocyclic group is substituted on a ringsulfur of the ‘heterocycle’, the sulfur is substituted with 1 or 2 oxogroups; R¹⁰ is selected from the group consisting of hydrogen, alkyl,alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heterocyclyl;R^(10a) is selected from the group consisting of alkyl, alkenyl,perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, andheterocyclyl; and R^(10b) is selected from the group consisting ofhydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl,heteroaryl, and heterocyclyl.
 2. The method as claimed in claim 1,wherein R¹ is selected from the group consisting of hydrogen,substituted- or unsubstituted-alkyl, substituted- orunsubstituted-alkenyl, substituted- or unsubstituted-cycloalkyl, andsubstituted- or unsubstituted-heterocyclyl.
 3. The method as claimed inclaim 1, wherein R¹ is selected from the group consisting of hydrogen,methyl, ethyl, isopropyl, allyl, difluoromethyl, cyclopropyl,3-oxetanyl, —CH₂COOC₂H₅, —CH₂CH(OH)CH₂(OH), and —C₂H₄OH.
 4. The methodas claimed in claim 1, wherein R³ and R⁴ are independently substituted-or unsubstituted-alkyl.
 5. The method as claimed in claim 1, wherein R³and R⁴ are methyl.
 6. The method as claimed in claim 1, wherein R^(a)and R^(b) are independently hydrogen or halogen.
 7. The method asclaimed in claim 1, wherein R^(a) and R^(b) are independently fluorineor iodine.
 8. The method as claimed in claim 1, wherein R^(c) and R^(d)are independently selected from the group consisting of hydrogen,substituted- or unsubstituted-alkyl, halogen, and hydroxyl; or R^(c) andR^(d) taken together with the carbon to which they are attached form asubstituted- or unsubstituted-cycloalkyl ring.
 9. The method as claimedin claim 1, wherein R^(c) and R^(d) are independently selected from thegroup consisting of hydrogen, methyl, fluoro, and hydroxyl; or R^(c) andR^(d) taken together with the carbon to which they are attached formcyclopropyl.
 10. The method as claimed in claim 1, wherein m is 1 or 2.11. The method as claimed in claim 1, wherein R⁶ and R⁷ areindependently selected from the group consisting of hydrogen,substituted- or unsubstituted-alkyl, substituted- orunsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl; or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached form a substituted- orunsubstituted-heterocycle.
 12. The method as claimed in claim 1, whereinR⁶ and R⁷ are independently selected from the group consisting ofhydrogen, methyl, cyclopropyl, and 3-oxetane; or R⁶ and R⁷ are takentogether with the nitrogen atom to which they are attached formazetidinyl or 3-hydroxyazetidinyl.
 13. The method as claimed in claim 1,wherein R⁸ and R⁹ are independently selected from the group consistingof hydrogen, substituted- or unsubstituted-cycloalkyl and substituted-or unsubstituted-heterocyclyl; or R⁸ and R⁹ taken together with thenitrogen to which they are attached form a substituted- orunsubstituted-heterocycle; with the provisos that both R⁸ and R⁹ are nothydrogen at the same time, and when R⁸ and R⁹ are not a part of aheterocycle formed together with the nitrogen to which they areattached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl.14. The method as claimed in claim 1, wherein R⁸ and R⁹ areindependently selected from the group consisting of hydrogen,cyclopropyl, cyclopropyl substituted with —C(═O)NH₂ or —CH₂OH,3-oxetanyl, tetrahydrofuran-3-yl, and tetrahydro-2H-pyranyl, or R⁸ andR⁹ taken together with the nitrogen to which they are attached form1,1-dioxidothiazolidinyl, 1,1-dioxidothiomorpholinyl, morpholinyl,azetidinyl, 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl,3-hydroxypyrrolidinyl or 4-hydroxypiperidinyl; with the provisos thatboth R⁸ and R⁹ are not hydrogen at the same time, and when R⁸ and R⁹ arenot a part of a heterocycle formed together with the nitrogen to whichthey are attached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl, or substituted- or unsubstituted-heterocyclyl.15. The method as claimed in claim 1, wherein: R¹ is selected from thegroup consisting of hydrogen, substituted- or unsubstituted-alkyl,substituted- or unsubstituted-alkenyl, and substituted- orunsubstituted-heterocyclyl; R³ and R⁴ are independently substituted- orunsubstituted-alkyl; R^(a) and R^(b) are independently hydrogen orhalogen; R^(c) and R^(d) are independently selected from the groupconsisting of hydrogen, substituted- or unsubstituted-alkyl, halogen,and hydroxyl, or R^(c) and R^(d) taken together with the carbon to whichthey are attached form a substituted- or unsubstituted-cycloalkyl ring;m is 1 or 2; R⁶ and R⁷ are independently selected from the groupconsisting of hydrogen, substituted- or unsubstituted-alkyl,substituted- or unsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl; or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached form a substituted- orunsubstituted-heterocycle; R⁸ and R⁹ are independently selected from thegroup consisting of hydrogen, substituted- or unsubstituted-cycloalkyland substituted- or unsubstituted-heterocyclyl, or R⁸ and R⁹ takentogether with the nitrogen to which they are attached form asubstituted- or unsubstituted-heterocycle; with the provisos that bothR⁸ and R⁹ are not hydrogen at the same time, and when R⁸ and R⁹ are nota part of a heterocycle formed together with the nitrogen to which theyare attached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl.16. The method as claimed in claim 1, wherein: R¹ is selected from thegroup consisting of hydrogen, methyl, ethyl, isopropyl, allyl,difluoromethyl, cyclopropyl, 3-oxetanyl, —CH₂COOC₂H₅, —CH₂CH(OH)CH₂(OH),and —C₂H₄OH; R³ and R⁴ are methyl; R^(a) and R^(b) are independentlyhydrogen, fluorine or iodine; R^(c) and R^(d) are independently selectedfrom the group consisting of hydrogen, methyl, fluoro, and hydroxyl, orR^(c) and R^(d) taken together with the carbon to which they areattached form a substituted- or unsubstituted-cyclopropyl; m is 1 or 2;R⁶ and R⁷ are independently selected from the group consisting ofmethyl, cyclopropyl, and 3-oxetane; or R⁶ and R⁷ taken together with thenitrogen atom to which they are attached form azetidinyl or3-hydroxyazetidinyl; R⁸ and R⁹ are independently selected from the groupconsisting of hydrogen, cyclopropyl, cyclopropyl substituted with—C(═O)NH₂ or —CH₂OH, 3-oxetanyl, tetrahydrofuran-3-yl, andtetrahydro-2H-pyranyl, or R⁸ and R⁹ are taken together with the nitrogento which they are attached form 1,1-dioxidothiazolidinyl,1,1-dioxidothiomorpholinyl, morpholinyl, azetidinyl, 1-pyrrolidinyl,piperazinyl, 4-methylpiperazinyl, 3-hydroxypyrrolidinyl or4-hydroxypiperidinyl; with the provisos that both R⁸ and R⁹ are nothydrogen at the same time, and when R⁸ and R⁹ are not a part of aheterocycle formed together with the nitrogen to which they areattached, at least one of the R⁸ and R⁹ is substituted- orunsubstituted-cycloalkyl or substituted- or unsubstituted-heterocyclyl.17. The method as claimed in claim 1, wherein a compound is selectedfrom the group consisting of:3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trion;N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide;N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide;N-(1-carbamoylcyclopropyl)-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide;3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;5-((2-fluoro-4-iodophenyl)amino)-1-(3-(4-hydroxypiperidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;N-cyclopropyl-3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-2-methylpropanamide;5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(4-methylpiperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;N-cyclopropyl-2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(pyrrolidine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide;3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide;N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;3-cyclopropyl-1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;3-cyclopropyl-1-(3--(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;N-cyclopropyl-3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide;2,2-difluoro-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;1-(3-(2-(azetidin-1-yl)-2-oxoethyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide;5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(oxetan-3-yl)benzamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide;3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydrofuran-3-yl)benzamide;3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide;3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-(1-(hydroxymethyl)cyclopropyl)benzamide;N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-(2-hydroxyethyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;N-cyclopropyl-2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide;3-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;N-cyclopropyl-3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-1l-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione;2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide;3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide;N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-isopropyl-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-3-(oxetan-3-yl)-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide;N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide;(R)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide;(S)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide;1-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl) cyclopropanecarboxamide;1-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetra hydropyrido[4,3-d]pyrimidin-1(2H)-yl) phenyl)cyclopropane carboxamide; and1-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide.